ALBERT

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Tao Li, Jing Li, Yang Yang, Yilin Han, Dirong Wu, Tao Xiao, Yang Wang, Ting Liu, Yonglong Zhao, Yongjun Li, Zeqin Dai, Xiaozhong Fu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono 〈span〉l〈/span〉-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na〈sup〉+〈/sup〉-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 〈strong〉6c〈/strong〉 as the optimal molecular candidate, with the highest antiviral activity (EC〈sub〉50〈/sub〉 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 〈strong〉6c〈/strong〉 exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 〈strong〉6c〈/strong〉 cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 〈strong〉6c〈/strong〉 indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and 〈span〉l〈/span〉-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 〈strong〉6c〈/strong〉 is a potential candidate as an anti-HBV therapy and therefore merits further investigation.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619309034-ga1.jpg" width="327" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Bo Hou, Ze Liu, Xiao-Bei Yang, Wen-Fei Zhu, Jin-Yu Li, Liu Yang, Fu-Cai Reng, Yong-Feng Lv, Jiang-Miao Hu, Guo-Yang Liao, Jun Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The stems of 〈em〉Dryopteris crassirhizoma〈/em〉, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin 〈strong〉ABBA〈/strong〉 is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 μM), it was very exciting that dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues (〈strong〉b5〈/strong〉 and 〈strong〉e2〈/strong〉) showed better NAs inhibitory activity against Anhui H7N9 with IC〈sub〉50〈/sub〉 values of 3.6 μM, 2.5 μM and 1.6 μM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin 〈strong〉ABBA〈/strong〉 and its analogues especially 〈strong〉AB〈/strong〉, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Total synthesis of dryocrassin ABBA and analogue structures with potential inhibitory activity against drug-resistant neuraminidases.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619308879-ga1.jpg" width="278" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Miriam Rossi, Francesco Caruso, Ilaria Costanzini, Carmen Kloer, Aron Sulovari, Elena Monti, Marzia Gariboldi, Emanuela Marras, Neduri V. Balaji, Modukuri V. Ramani, Gottumukkala V. Subbaraju〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619301907-ga1.jpg" width="366" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Zahra Mojallal-Tabatabaei, Parham Foroumadi, Mahsa Toolabi, Fereshteh Goli, Setareh Moghimi, Sussan Kaboudanian-Ardestani, Alireza Foroumadi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of 〈em〉Leishmania major〈/em〉 (〈em〉L. major)〈/em〉. Amongst the synthesized compounds, 2-([1,4′-bipiperidin]-1′-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (〈strong〉IIa〈/strong〉) and 1-(5-(1-methyl-5-nitro-1〈em〉H〈/em〉-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (〈strong〉IIc〈/strong〉) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of 〈em〉L. major〈/em〉 cells to 〈strong〉IIa〈/strong〉 and 〈strong〉IIc〈/strong〉 led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of 〈strong〉IIa〈/strong〉 and 〈strong〉IIc〈/strong〉 is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619303700-ga1.jpg" width="335" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Shweta Sinha, Mukesh Doble, S.L. Manju〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306777-ga1.jpg" width="412" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Fa-Qian Shen, Lu Shi, Ze-Feng Wang, Chen-Ru Wang, Jin-Jin Chen, Yi Liu, Han-Yue Qiu, Hai-Liang Zhu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉For the purpose of synthesizing drug candidates with desirable bioactivity, a class of benzoyl amide containing nitrogen heterocyclic ring derivatives targeting VEGFR-2 was designed and screened out using Discovery Studio. Eighteen target compounds were synthesized and then selected by some biological trials sequentially including inhibition of VEGFR-2, anti-proliferation in vitro, flow cytometry. Among them, compound 〈strong〉8h〈/strong〉 showed the best inhibitory activity (IC〈sub〉50〈/sub〉 = 0.34 ± 0.02 μM against VEGFR-2, IC〈sub〉50〈/sub〉 = 1.08 ± 0.06 μM and 2.44 ± 0.15 μM against MCF-7 and HepG-2, respectively, which were at the same inhibitory level with the commercially antitumor drug: vandetanib). In addition, flow cytometry demonstrated that compound 〈strong〉8h〈/strong〉 induced MCF-7 cell apoptosis through a cell membrane-mediated pathway. This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619304043-ga1.jpg" width="353" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈p〉Binding mode of compound 〈strong〉8h〈/strong〉 with VEGFR-2 (PDB code: 〈strong〉4ASD〈/strong〉). The 3D diagram of the interaction between compound 〈strong〉8h〈/strong〉 and key amino acid residues.〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): George Amato, Robert Wiethe, Amruta Manke, Vineetha Vasukuttan, Rodney Snyder, Scott Runyon, Rangan Maitra〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (〈strong〉1〈/strong〉) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (〈strong〉2〈/strong〉) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 〈strong〉1〈/strong〉 are explored to develop and test strategies for peripheralization. The piperidine of 〈strong〉1〈/strong〉 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 〈strong〉75〈/strong〉 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306431-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 17〈/p〉 〈p〉Author(s): Pedro Silvino Pereira, Maria do Carmo Alves de Lima, Pedro Paulo Marcelino Neto, Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino, Irwin Rose de Alencar Menezes, Jamerson Ferreira de Oliveira, Pascal Marchand, Henrique Douglas Melo Coutinho, Maria do Desterro Rodrigues, Teresinha Gonçalves da Silva〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the 〈em〉Staphylococcus aureus〈/em〉 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the 〈em〉in silico〈/em〉 study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC 〉 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent 〈em〉in vitro〈/em〉 inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of −9.03 Kcal/mol and −9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against 〈em〉S. aureus〈/em〉 SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961930481X-ga1.jpg" width="267" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 16〈/p〉 〈p〉Author(s): Tamila Galaka, Bruno N. Falcone, Catherine Li, Sergio H. Szajnman, Silvia N.J. Moreno, Roberto Docampo, Juan B. Rodriguez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against 〈em〉Trypanosoma cruzi〈/em〉 and 〈em〉Toxoplasma gondii〈/em〉, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 〈strong〉21〈/strong〉–〈strong〉33〈/strong〉), that is, the position of the amino group was one carbon closer to the 〈em〉gem〈/em〉-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of 〈em〉T. cruzi〈/em〉. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 〈strong〉47〈/strong〉–〈strong〉49〈/strong〉 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 〈strong〉54〈/strong〉–〈strong〉56〈/strong〉, 〈strong〉59〈/strong〉, turned out to be nanomolar growth inhibitors of tachyzoites of 〈em〉T. gondii〈/em〉. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619307400-ga1.jpg" width="413" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Hong Chen, Jingxiao Zhang, Peixin Hu, Yuna Qian, Jing Li, Jianliang Shen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (〈strong〉3〈/strong〉, 〈strong〉4〈/strong〉, 〈strong〉5〈/strong〉, 〈strong〉7〈/strong〉, 〈strong〉8〈/strong〉, 〈strong〉10〈/strong〉, 〈strong〉11〈/strong〉, 〈strong〉12〈/strong〉, 〈strong〉16〈/strong〉, 〈strong〉18〈/strong〉, 〈strong〉21〈/strong〉, 〈strong〉23〈/strong〉, and 〈strong〉24〈/strong〉) exhibited potent antagonistic potency against AR (inhibition 〉50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) 〈em〉versus〈/em〉 PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 〈strong〉23〈/strong〉 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619311836-ga1.jpg" width="320" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Rostislav Kuskovsky, Dina Lloyd, Kriti Arora, Balbina J. Plotkin, Jacalyn M. Green, Helena I. Boshoff, Clifton Barry, Jeffrey Deschamps, Monika I. Konaklieva〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉C4-phenylthio β-lactams are a new family of antibacterial agents that have activity against two phylogenetically distant bacteria – 〈em〉Mycobacterium tuberculosis〈/em〉 (Mtb) and 〈em〉Moraxella catarrhalis〈/em〉 (M. cat). These compounds are effective against β-lactamase producing Mtb and M. cat unlike the clinically relevant β-lactam antibiotics. The structure-activity relationship for the C4 phenylthio β-lactams has not yet been completely defined. Earlier efforts in our laboratories established that the C4-phenylthio substituent is essential for antimicrobial activity, while the N1 carbamyl substituent plays a more subtle role. In this present study, we investigated the role that the stereochemistry at C4 plays in these compounds’ antibacterial activity. This was achieved by synthesizing and testing the antimicrobial activity of diastereomers with a chiral carbamyl group at N1. Our findings indicate that a strict stereochemistry for the C4-phenylthio β-lactams is not required to obtain optimal anti-Mtb and anti-M. cat activity. Furthermore, the structure–bioactivity profiles more closely relate to the electronic requirement of the phenylthiogroup. In addition, the MICs of Mtb are sensitive to growth medium composition. Select compounds showed activity against non-replicating and multi-drug resistant Mtb.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619307539-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 21 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Hongrui Lei, Fang Jia, Meng Cao, Jie Wang, Ming Guo, Minglin Zhu, Daiying Zuo, Xin Zhai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives. Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the ‘semi-free urea’ compound 〈strong〉39〈/strong〉. All compounds were assayed cytotoxicity and enzymatic activities and 〈strong〉39〈/strong〉 turned out to be the most potent one with IC〈sub〉50〈/sub〉 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALK〈sup〉wt〈/sup〉, ALK〈sup〉L1196M〈/sup〉, ALK〈sup〉G1202R〈/sup〉 and ROS1, respectively. The performances of 〈strong〉39〈/strong〉 on ALK- & ROS1-dependent cell lines were in good accordance with enzymatic activities with IC〈sub〉50〈/sub〉 values below 0.06 µM. Besides, 〈strong〉39〈/strong〉 induced cell apoptosis in a dose-dependent manner in H2228 cells. Finally, the binding models of 〈strong〉39〈/strong〉 with ALK〈sup〉wt〈/sup〉, ROS1, ALK〈sup〉L1196M〈/sup〉 and ALK〈sup〉G1202R〈/sup〉 were ideally established which further clearly elucidated their mode of action within the active site.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619311228-ga1.jpg" width="401" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Juliana C. Gomes, Lorenzo Cianni, Jean Ribeiro, Fernanda dos Reis Rocho, Samelyn da Costa Martins Silva, Pedro Henrique Jatai Batista, Carolina Borsoi Moraes, Caio Haddad Franco, Lucio H.G. Freitas-Junior, Peter W. Kenny, Andrei Leitão, Antonio C.B. Burtoloso, Daniela de Vita, Carlos A. Montanari〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly non-additive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the non-additivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310041-ga1.jpg" width="369" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Damian A. Madrigal, Carlos H. Escalante, Gabriel A. Gutiérrez-Rebolledo, José M. Cristobal-Luna, Omar Gómez-García, Roberto I. Hernández-Benitez, Ana L. Esquivel-Campos, Salud Pérez-Gutiérrez, Germán A. Chamorro-Cevallos, Francisco Delgado, Joaquín Tamariz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Since NSAIDs are commonly used anti-inflammatory agents that produce adverse effects, there have been ongoing efforts to develop more effective and less toxic compounds. Based on the structure of the anti-inflammatory pyrrolizines licofelone and ketorolac, a series of 1-arylpyrrolizin-3-ones was synthesized. Also prepared was a series of substituted pyrroles, mimicking similar known anti-inflammatory agents. The anti-inflammatory activity of the test compounds was determined with a phorbol ester (TPA)-induced murine ear edema protocol. For the most active derivatives, 〈strong〉19b〈/strong〉–〈strong〉c〈/strong〉/〈strong〉20b〈/strong〉–〈strong〉c〈/strong〉, the anti-inflammatory effect was the same as that of the reference compound (indomethacin) and was dose-dependent. These compounds have an aryl ring at the C-1 position and a methoxycarbonyl group at the C-2 position of the pyrrolizine framework, which represent plausible pharmacophore groups with anti-inflammatory activity. The anti-inflammatory activity of 1-substituted analogs containing a five- or six-membered heterocycles was lower but still good, while that of the pyrroles was only moderate. Although the docking studies suggests that the effect of analogs 〈strong〉19a〈/strong〉–〈strong〉c〈/strong〉/〈strong〉20a〈/strong〉–〈strong〉c〈/strong〉 is associated with the inhibition of cyclooxygenase-2, experimental assays did not corroborate this idea. Indeed, a significant inhibition of NO was found experimentally as a plausible mechanism of action.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619305036-ga1.jpg" width="400" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Jana Deitersen, Dina H. El-Kashef, Peter Proksch, Björn Stork〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In order to overcome therapy resistance in cancer, scientists search in nature for novel lead structures for the development of improved chemotherapeutics. Anthraquinones belong to a class of tricyclic organic natural compounds with promising anti-cancer effects. Anthraquinone derivatives are rich in structural diversity, and exhibit pleiotropic properties, among which the modulation of autophagy seems promising in the context of overcoming cancer-therapy resistance. Among the most promising derivatives in this regard are emodin, aloe emodin, rhein, physcion, chrysophanol and altersolanol A. On the molecular level, these compounds target autophagy via different upstream pathways including the AKT/mTOR-axis and transcription of autophagy-related proteins. The role of autophagy is pro-survival as well as cell death-promoting, depending on derivatives and their cell type specificity. This review summarizes observed effects of anthraquinone derivatives on autophagy and discusses targeted pathways and crosstalks. A cumulative knowledge about this topic paves the way for further research on modes of action, and aids to find a therapeutic window of anthraquinones in cancer-therapy.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619305292-ga1.jpg" width="186" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Rick Raudszus, Robert Nowotny, Christoph G.W. Gertzen, Andrea Schöler, Andor Krizsan, Ines Gockel, Hermann Kalwa, Holger Gohlke, René Thieme, Finn K. Hansen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fluorescent tagging of bioactive molecules is a powerful tool to study cellular uptake kinetics and is considered as an attractive alternative to radioligands. In this study, we developed fluorescent histone deacetylase (HDAC) inhibitors and investigated their biological activity and cellular uptake kinetics. Our approach was to introduce a dansyl group as a fluorophore in the solvent-exposed cap region of the HDAC inhibitor pharmacophore model. Three novel fluorescent HDAC inhibitors were synthesized utilizing efficient submonomer protocols followed by the introduction of a hydroxamic acid or 2-aminoanilide moiety as zinc-binding group. All compounds were tested for their inhibition of selected HDAC isoforms, and docking studies were subsequently performed to rationalize the observed selectivity profiles. All HDAC inhibitors were further screened in proliferation assays in the esophageal adenocarcinoma cell lines OE33 and OE19. Compound 〈strong〉2〈/strong〉, 6-((〈em〉N〈/em〉-(2-(benzylamino)-2-oxoethyl)-5-(dimethylamino)naphthalene)-1-sulfonamido)-〈em〉N〈/em〉-hydroxyhexanamide, displayed the highest HDAC inhibitory capacity as well as the strongest anti-proliferative activity. Fluorescence microscopy studies revealed that compound 〈strong〉2〈/strong〉 showed the fastest uptake kinetic and reached the highest absolute fluorescence intensity of all compounds. Hence, the rapid and increased cellular uptake of 〈strong〉2〈/strong〉 might contribute to its potent anti-proliferative properties.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619304778-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 3 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Ronnakorn Leechaisit, Ratchanok Pingaew, Veda Prachayasittikul, Apilak Worachartcheewan, Supaluk Prachayasittikul, Somsak Ruchirawat, Virapong Prachayasittikul〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A library of bis-sulfonamides (〈strong〉9〈/strong〉–〈strong〉26〈/strong〉) were synthesized and tested for their aromatase inhibitory activities. Interestingly, all bis-sulfonamide derivatives inhibited the aromatase with IC〈sub〉50〈/sub〉 range of 0.05–11.6 μM except for compound 〈strong〉23〈/strong〉. The analogs 〈strong〉15〈/strong〉 and 〈strong〉16〈/strong〉 bearing hydrophobic chloro and bromo groups exhibited the potent aromatase inhibitory activity in sub-micromolar IC〈sub〉50〈/sub〉 values (i.e., 50 and 60 nM, respectively) with high safety index. Molecular docking revealed that the chloro and bromo benzenesulfonamides (〈strong〉15〈/strong〉 and 〈strong〉16〈/strong〉) may play role in the hydrophobic interaction with Leu477 of the aromatase to mimic steroidal backbone of the natural substrate, androstenedione. QSAR study also revealed that the most potent activity of compounds was governed by van der Waals volume (GATS6v) and mass (Mor03m) descriptors. Finally, the two compounds (〈strong〉15〈/strong〉 and 〈strong〉16〈/strong〉) were highlighted as promising compounds to be further developed as novel aromatase inhibitors.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310028-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 19 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Yinda Qiu, Zhongxiang Xiao, Yanyan Wang, Dingfang Zhang, Wenxin Zhang, Guangbao Wang, Wenbin Chen, Guang Liang, Xiaokun Li, Yali Zhang, Zhiguo Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Myeloid differentiation protein 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) responsible for the recognition of lipopolysaccharide (LPS) and mediates a series of TLR4-dependent inflammatory responses in inflammatory lung diseases including acute lung injury (ALI). Targeting MD2 thus may provide a therapeutic strategy against these lung diseases. In this study, we identified a novel compound 〈strong〉4k〈/strong〉 with the potent anti-inflammatory activity among 39 methyl gallate derivatives (MGDs). MGD 〈strong〉4k〈/strong〉 exhibited a high binding affinity to MD2, which in turn prevented the formation of the LPS/MD2/TLR4 complex. In addition, MGD 〈strong〉4k〈/strong〉 significantly reversed the upregulation of LPS-induced inflammatory mediators such as tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. Mechanistically, MGD 〈strong〉4k〈/strong〉 performed anti-inflammatory function by inactivating JNK, ERK and p38 signaling pathways. Taken together, our study identified MGD 〈strong〉4k〈/strong〉 as a novel potential therapeutic agent for ALI through inhibiting MD2, inflammatory responses, and major inflammation-associated signaling pathways.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Novel methyl gallate derivatives were synthesized, and evaluated their anti-inflammatory activities for the treatment of ALI as MD2 inhibitors.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306297-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 14 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Ravi P. Singh, Marian N. Aziz, Delphine Gout, Walid Fayad, May A. El-Manawaty, Carl J. Lovely〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of N-substituted (〈em〉Z〈/em〉)-2-imino-(5〈em〉Z〈/em〉)-ylidene thiazolidines/thiazolidin-4-ones were synthesized and their antiproliferative activities against colon (HCT-116) and breast (MCF7) cancer cell lines were evaluated utilizing an MTT growth assay. A 2D-QSAR investigation was conducted to probe and validate the obtained antiproliferative properties for the thiazolidine derivatives. The majority of the thiazolidines exhibit higher potency against a colon cancer cell line relative to the standard reference. The 〈em〉p〈/em〉-halophenylimino 〈em〉p〈/em〉-anisylidene derivatives exhibited the highest anti-proliferative activity against HCT116 relative to control (IC〈sub〉50〈/sub〉 = 8.9–10.0 μM compared to 20.4 μM observed for 5-fluorouracil as positive control). An X-ray study confirmed the 〈em〉Z〈/em〉, 〈em〉Z〈/em〉′-configurations for two examples of the synthesized compounds.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306030-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 9 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Annalisa Reale, Simone Brogi, Alessia Chelini, Marco Paolino, Angela Di Capua, Germano Giuliani, Andrea Cappelli, Gianluca Giorgi, Giulia Chemi, Alessandro Grillo, Massimo Valoti, Lidia Sautebin, Antonietta Rossi, Simona Pace, Concettina La Motta, Lorenzo Di Cesare Mannelli, Elena Lucarini, Carla Ghelardini, Maurizio Anzini〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (〈strong〉10〈/strong〉–〈strong〉12〈/strong〉) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect.〈/p〉 〈p〉Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (〈strong〉9a-c)〈/strong〉 into the corresponding alkyl thioethers (〈strong〉10a-c〈/strong〉) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 〈strong〉10a,b〈/strong〉 were also investigated and both couple of sulfoxides (〈strong〉11a〈/strong〉,〈strong〉b〈/strong〉) and sulfones (〈strong〉12a〈/strong〉,〈strong〉b〈/strong〉) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 〈strong〉10b〈/strong〉, 〈strong〉11b〈/strong〉, and 〈strong〉12b〈/strong〉 into COX-2 enzyme and to explore the potential site of metabolism of 〈strong〉10a〈/strong〉 and 〈strong〉10b〈/strong〉 due to the different 〈em〉in vivo〈/em〉 efficacy. Among the developed compounds, compound 〈strong〉10b〈/strong〉 showed a significant 〈em〉in vivo〈/em〉 anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961931079X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 9 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Toshinori Suzuki, Yuki Kishida〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉When a neutral solution of thymidine and ascorbic acid was irradiated with UV light of wavelength longer than 300 nm in the presence of salicylic acid as a photosensitizer, six product peaks appeared in an HPLC chromatogram in addition to small amounts of thymidine dimers. The six products were identified as three pairs of diastereomers of 5-(2-deoxy-2-〈span〉l〈/span〉-ascorbyl)-5,6-dihydrothymidine, 5-(2-〈span〉l〈/span〉-ascorbyl)-5,6-dihydrothymidine, and 5,6-dihydrothymidine. These results suggest that novel DNA damage may be generated by ascorbic acid with salicylic acid induced by sunlight.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619311423-ga1.jpg" width="312" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Chenyin Wang, Laura Engelke, David Bickel, Alexandra Hamacher, Marian Frank, Peter Proksch, Holger Gohlke, Matthias U. Kassack〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Platinum compounds are the first-line therapy for many types of cancer. However, drug resistance has frequently been reported for and is a major limitation of platinum-based chemotherapy in the clinic. In the current study, we examined the anti-tumor activity of phomoxanthone A (PXA), a tetrahydroxanthone dimer isolated from the endophytic fungus 〈em〉Phomopsis longicolla〈/em〉, in several solid cancer cell lines and their cisplatin-resistant sub-cell lines. PXA showed strong cytotoxic effects with IC〈sub〉50〈/sub〉 values in the high nanomolar or low micromolar range in MTT assays. IC〈sub〉50〈/sub〉 values of PXA were lower than those of cisplatin. Remarkably, equipotent anti-cancer activity was found in cisplatin-sensitive and respective cisplatin-resistant cells. Anticancer effects of PXA were studied in further detail in ovarian cancer (A2780) and bladder cancer (J82) cell pairs. PXA led to rapid depolarization of the mitochondrial membrane potential and strong activation of caspase 3 and 7, eventually resulting in strong induction of apoptosis. These effects occurred again both in sensitive and resistant cell lines. IC〈sub〉50〈/sub〉 values of PXA from MTT and mitochondrial membrane depolarization assays were in good agreement. Configurational free energy computations indicate that both the neutral and singly negatively charged PXA show membrane partitioning and can penetrate the inner mitochondrial membrane. PXA treatment did not damage the plasma membranes of cancer cells, thus excluding unspecific membrane effects. Further, PXA had neither an effect on intracellular ROS nor on reduction of ROS after hydrogen peroxide treatment. In conclusion, our studies present PXA as a natural compound with strong apoptotic anticancer effects against platinum-resistant solid cancers. This may open new treatment options in clinically resistant malignancies.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619307850-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 7 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Marc Pflieger, Alexandra Hamacher, Taner Öz, Nadine Horstick-Muche, Benedikt Boesen, Christian Schrenk, Matthias U. Kassack, Thomas Kurz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of α,β-unsaturated hydroxamic acid derivatives as novel HDAC inhibitors (HDACi) with structural modifications of the connecting unit and the CAP group was synthesized. The 〈em〉in vitro〈/em〉 evaluation against the human cancer cell lines A2780 and Cal27 identified 〈strong〉6e〈/strong〉 and 〈strong〉7j〈/strong〉 as the most potent compounds regarding HDAC inhibitory activity and inhibition of proliferation. Isoform profiling against HDAC2, 4, 6 and 8 revealed a preference for HDAC2 and 6 for both compounds in contrast to the pan HDACi panobinostat. 〈strong〉6e〈/strong〉 and 〈strong〉7j〈/strong〉 enhanced significantly cisplatin-induced cytotoxicity in a combination treatment mediated by increased apoptosis induction and caspase-3/7 activation. The interaction between 〈strong〉6e〈/strong〉 or 〈strong〉7j〈/strong〉 and cisplatin was highly synergistic and more pronounced for the cisplatin resistant subline Cal27CisR. IC〈sub〉50〈/sub〉 values of cisplatin were even lower in Cal27CisR pretreated with 〈strong〉6e〈/strong〉 or 〈strong〉7j〈/strong〉 than for the parental cell line Cal27. Based on our findings, the novel dual class I/HDAC6 inhibitors could serve as an option to overcome cisplatin resistance with fewer side effects in comparison to panobinostat.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961930522X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 7 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Patrick M. Wehrli, Ivana Uzelac, Thomas Olsson, Tomas Jacso, Daniel Tietze, Johan Gottfries〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉High-throughput screening of small-molecule libraries has led to the identification of thiadiazoles as a new class of inhibitors against 〈em〉Staphylococcus aureus〈/em〉 sortase A (SrtA). N-(5-((4-nitrobenzyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide (IC〈sub〉50〈/sub〉 = 3.8 µM) was identified as a potent inhibitor of SrtA after synthetic modification of hit compounds. Additional ligands developed in this study displayed affinities in the low micromolar range without affecting bacterial growth 〈em〉in vitro〈/em〉. The study also suggest a new mode of action through covalent binding to the active site cysteine.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619303943-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Orit Jacobson, Zhantong Wang, Guocan Yu, Ying Ma, Xiaoyuan Chen, Dale O. Kiesewetter〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉The efficient radiosynthesis of biomolecules utilizing minute quantities of maleimide substrate is important for availability of novel peptide molecular imaging agents. We evaluated both 3-〈sup〉18〈/sup〉F-fluoropropane-1-thiol and 2-(2-(2-(2-〈sup〉18〈/sup〉F-fluoroethoxy)ethoxy)ethoxy)ethane-1-thiol (〈sup〉18〈/sup〉F-fluoro-PEG〈sub〉4〈/sub〉 thiol) as prosthetic groups for radiolabeling under physiological conditions. The precursor employed a benzoate for protection of the thiol and an arylsulfonate leaving group. The radiofluorination was fully automated on an Eckert & Ziegler synthesis system using standard Kryptofix〈sub〉222〈/sub〉/K〈sub〉2〈/sub〉CO〈sub〉3〈/sub〉 conditions. In order to minimize the amount of biological molecule required for subsequent conjugation, the intermediates, S-(3-〈sup〉18〈/sup〉F-fluoropropyl) benzothioate and 〈sup〉18〈/sup〉F-fluoro-PEG〈sub〉4〈/sub〉 benzothioate, were purified by HPLC. The intermediates were isolated from the HPLC in yields of 37–47% and 28–35%, respectively, and retrieved from eluate using solid phase extraction. Treatment of the benzothioates with sodium methoxide followed by acetic acid provided the free thiols. The desired maleimide substrate in acetonitrile or phosphate buffer was then added and incubated at room temperature for 15 min. The final radiolabeled bioconjugate was purified on a separate HPLC or NAP-5 column. Maleimides utilized for the coupling reaction included phenyl maleimide, an Evans Blue maleimide derivative, a dimeric RGDfK maleimide (E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉), two aptamer maleimides, and PSMA maleimide derivative. Isolated radiochemical yields (non-decay corrected) of maleimide addition products based on starting 〈sup〉18〈/sup〉F-fluoride ranged from 6 to 22% in a synthesis time of about 90 min.〈/p〉 〈p〉〈sup〉18〈/sup〉F-thiol prosthetic groups were further tested 〈em〉in vivo〈/em〉 by conjugation to E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉 maleimide in a U87MG xenograft model. PET studies demonstrated similar tumor accumulation of both prosthetic groups. 〈sup〉18〈/sup〉F-fluoro-PEG〈sub〉4〈/sub〉-S-E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉 displayed a somewhat favorable pharmacokinetics compared to 〈sup〉18〈/sup〉F-fluoropropyl-S-E[〈em〉c〈/em〉(〈em〉RGDfK〈/em〉)]〈sub〉2〈/sub〉. Bone uptake was low for both indicating 〈em〉in vivo〈/em〉 stability.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310661-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 18〈/p〉 〈p〉Author(s): Jaiprakash Sangshetti, Shahebaaz K. Pathan, Rajesh Patil, Siddique Akber Ansari, Santosh Chhajed, Rohidas Arote, Devanand B. Shinde〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310193-ga1.jpg" width="399" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 18〈/p〉 〈p〉Author(s): Daisuke Mori, Hiroyuki Kimura, Hidekazu Kawashima, Yusuke Yagi, Kenji Arimitsu, Masahiro Ono, Hideo Saji〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (〈sup〉99m〈/sup〉Tc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4β2-nAChR agonist, we prepared A85380 derivatives labeled with 〈sup〉99m〈/sup〉Tc using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a 〈sup〉99m〈/sup〉Tc analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at α4β2-nAChR in both the docking simulation (−19.3 kcal/mol) and binding assay (Ki = 0.4 ± 0.04 nM). Further, 〈sup〉99m〈/sup〉Tc-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that 〈sup〉99m〈/sup〉Tc-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR 〈em〉in vitro〈/em〉 and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619304183-ga1.jpg" width="279" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 31 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Yifan Feng, Weiming Duan, Shu Fan, Hao Zhang, San-Qi Zhang, Minhang Xin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds 〈strong〉A5〈/strong〉 and 〈strong〉A8〈/strong〉 were identified as potent PI3Kδ inhibitors, with IC〈sub〉50〈/sub〉 values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC〈sub〉50〈/sub〉 = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound 〈strong〉A5〈/strong〉 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. 〈strong〉A8〈/strong〉 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds 〈strong〉A5〈/strong〉 and 〈strong〉A8〈/strong〉 selectively exhibited anti-proliferation against SU-DHL-6 〈em〉in vitro〈/em〉 with IC〈sub〉50〈/sub〉 values of 0.16 and 0.12 μM. Western blot analysis indicated that 〈strong〉A8〈/strong〉 could attenuate the AKT〈sup〉S473〈/sup〉 phosphorylation. Molecular docking study suggested that 〈strong〉A8〈/strong〉 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619310065-ga1.jpg" width="448" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 27, Issue 18〈/p〉 〈p〉Author(s): Xiaoman Zheng, Zhengfeng Fu, Chunyun Wang, Shengbo Zhang, Min Dai, Enbo Cai, Yan Zhao〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Objective〈/h6〉 〈p〉To study the changes of ginsenoside content in different proportion of 〈em〉Panax ginseng-Angelica sinensis〈/em〉 (GA) co-decoction, and to explore the amelioration of hematopoietic function in mice after combined use of the two drugs. The active ingredient profiles in 〈em〉P. ginseng〈/em〉 single decoction and co-decoction of GA were determined by high performance liquid chromatography (HPLC). The experimental pharmacology method was used to explore the effect of GA co-decoction on the hematopoietic function of chemotherapy mice.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉The active ingredient profiles of the co-decoction of GA significantly changed compared with those of the single decoction. Compared with GA1:0 (single decoction of 〈em〉Panax ginseng〈/em〉), the routine ginsenosides of all proportions of GA decreased significantly, but the proportion of rare ginsenosides increased significantly. The changes of contents of rare ginsenosides of GA were basically consistent with the trends of effects on the myelosuppression induced by CY. Compared with the model group, GA significantly increased the number of bone marrow nucleated cells, thymus index, peripheral blood leukocytes and platelets, and significantly reduced the spleen index. Moreover, GA could promote G1 phase bone marrow cells to enter the cell cycle, increase the proportion of S phase cells and G2/M phase cells, and increase the cell proliferation index.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusion〈/h6〉 〈p〉GA can ameliorate the hematopoietic function of mice after chemotherapy, and GA2:3, GA3:2 were the best, which may be due to the changes of the pharmacodynamic material basis of GA after compatibility. All these results implied that GA may be an ideal drug and food supplement for the treatment of toxic and side effects of chemotherapeutic drugs.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619306844-ga1.jpg" width="367" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 19 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Richa Mishra, Soumendra Rana〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The human complement fragment 5a (〈sup〉h〈/sup〉C5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and non-immunological responses in humans. Dysregulation of complement system is associated with the upregulation of 〈sup〉h〈/sup〉C5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, 〈sup〉h〈/sup〉C5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of 〈sup〉h〈/sup〉C5a. However, the idea of small molecules, directly neutralizing the function of excessive 〈sup〉h〈/sup〉C5a remains unexplored in the literature. By recruiting cheminformatics approach, the avenue of drug repositioning is explored in the current study for discovering novel neutraligands of 〈sup〉h〈/sup〉C5a. The systematic exercise yields a pool of potential neutraligands, from which four FDA approved drugs, such as carprofen, oxaprozin, sulindac and raloxifene have been subjected to a battery of computational and biophysical studies against 〈sup〉h〈/sup〉C5a. The data obtained from docking, molecular dynamics, and molecular mechanics Poisson-Boltzmann surface area studies, strongly correlate with the data obtained from the circular dichroism, steady state fluorescence, and fluorescence quenching studies, involving the recombinant 〈sup〉h〈/sup〉C5a and the selected drugs. The proof of the concept study successfully documents the rational discovery of first generation template neutraligands of 〈sup〉h〈/sup〉C5a through drug repositioning approach and suggests that the selected drugs perhaps bind functionally distinct hot spots on 〈sup〉h〈/sup〉C5a. The identified neutraligands can be subsequently optimized as complement specific therapeutics for strongly modulating the 〈sup〉h〈/sup〉C5a-C5aR signaling axes.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619305541-ga1.jpg" width="317" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Gang Xing, Li Pan, Ce Yi, Xiaoran Li, Xinyue Ge, Ying Zhao, Yichuang Liu, Jinyan Li, Anthony Woo, Bin Lin, Yuyang Zhang, Maosheng Cheng〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of novel β〈sub〉2〈/sub〉-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1〈em〉H〈/em〉)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 〈strong〉9g〈/strong〉 and 〈strong〉(R)-18c〈/strong〉 exhibited the most excellent β〈sub〉2〈/sub〉-adrenoceptor agonistic effects and high β〈sub〉2〈/sub〉/β〈sub〉1〈/sub〉-selectivity with EC〈sub〉50〈/sub〉 values of 36 pM for 〈strong〉9g〈/strong〉 and 21 pM for 〈strong〉(R)-18c〈/strong〉. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an 〈em〉in vitro〈/em〉 guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618316870-ga1.jpg" width="449" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 22〈/p〉 〈p〉Author(s): Elisabetta Barresi, Chiara Giacomelli, Simona Daniele, Ilaria Tonazzini, Marco Robello, Silvia Salerno, Ilaria Piano, Barbara Cosimelli, Giovanni Greco, Federico Da Settimo, Claudia Martini, Maria Letizia Trincavelli, Sabrina Taliani〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the 〈em〉N〈/em〉〈sup〉1〈/sup〉 (〈strong〉1〈/strong〉,〈strong〉2〈/strong〉) or 〈em〉N〈/em〉〈sup〉10〈/sup〉 (〈strong〉3〈/strong〉,〈strong〉4〈/strong〉) nitrogen of a triazinobenzimidazole scaffold, were synthesized. The compounds were biologically evaluated as fluorescent probes for labelling A〈sub〉1〈/sub〉 and A〈sub〉2B〈/sub〉 AR subtypes in bone marrow-derived mesenchymal stem cells (BM-MSCs) that express both receptor subtypes. The binding affinity of the synthetized compounds towards the different AR subtypes was determined. The probe 〈strong〉3〈/strong〉 revealed a higher affinity to A〈sub〉1〈/sub〉 and A〈sub〉2B〈/sub〉 ARs, showing interesting spectroscopic properties, and it was selected as the most suitable candidate to label both AR subtypes in undifferentiated MSCs.〈/p〉 〈p〉Fluorescence confocal microscopy showed that compound 〈strong〉3〈/strong〉 significantly labelled ARs on cell membranes and the fluorescence signal was decreased by the cell pre-incubation with the A〈sub〉1〈/sub〉 AR and A〈sub〉2B〈/sub〉 AR selective agonists, R-PIA and BAY 60-6583, respectively, thus confirming the specificity of the obtained signal. In conclusion, compound 〈strong〉3〈/strong〉 could represent a useful tool to investigate the expression pattern of both A〈sub〉1〈/sub〉 and A〈sub〉2B〈/sub〉 ARs in different pathological and physiological processes. Furthermore, these results provide an important basis for the design of new and more selective derivatives able to monitor the expression and localization of each different ARs in several tissues and living cells.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618313683-ga1.jpg" width="395" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Danielle Cristina Zimmermann-Franco, Bruna Esteves, Leticia Moroni Lacerda, Isabela de Oliveira Souza, Juliana Alves dos Santos, Nícolas de Castro Campos Pinto, Elita Scio, Adilson David da Silva, Gilson Costa Macedo〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Resveratrol is a natural polyphenol found mainly on red grapes and in red wine, pointed as an important anti-inflammatory/immunomodulatory molecule. However, its bioavailability problems have limited its use encouraging the search for new alternatives agents. Thus, in this study, we synthetize 12 resveratrol analogues (6 imines, 1 thioimine and 5 hydrazones) and investigated its cytotoxicity, antioxidant activity and 〈em〉in vitro〈/em〉 anti-inflammatory/immunomodulatory properties. The most promising compounds were also evaluated 〈em〉in vivo〈/em〉. The results showed that imines presented less cytotoxicity, were more effective than resveratrol on DPPH scavenger and exhibited an anti-inflammatory profile. Among them, the imines with a radical in the 〈em〉para〈/em〉 position, on the ring B, not engaged in an intramolecular hydrogen-interaction, showed more prominent anti-inflammatory activity modulating, 〈em〉in vivo〈/em〉, the edema formation, the inflammatory infiltration and cytokine levels. An immunomodulatory activity also was observed in these molecules. Thus, our results suggest that imines with these characteristics presents potential to control inflammatory disorders.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618308848-ga1.jpg" width="494" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Yuko Kazui, Shinya Fujii, Ayumi Yamada, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Aya Tanatani〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The androgen receptor (AR) is a ligand-inducible transcription factor belonging to the nuclear receptor superfamily, and is a target molecule for development of drugs to treat prostate cancer. However, AR antagonists in clinical use, such as flutamide (〈strong〉3a〈/strong〉) and bicalutamide (〈strong〉4〈/strong〉), encounter resistance after several years of hormone therapy, predominantly due to mutations of AR. Thus, although some new-generation AR antagonists have been developed, novel types of AR antagonists are still required to treat drug-resistant prostate cancer. We previously reported a novel (benzoylaminophenoxy)phenol derivative 〈strong〉10a〈/strong〉, which is structurally distinct from conventional AR antagonists. Here, we systematically examined the structure–activity relationship of (benzoylaminophenoxy)phenol derivatives on the inhibitory activity on the prostate cancer cell proliferations. We found that the 4-[4-(benzoylamino)phenoxy]phenol backbone is important for anti-prostate cancer activity. Introduction of a small substituent at the 2 position of the central benzene ring (B ring) increases the activity. Among the synthesized compounds, 〈strong〉19a〈/strong〉 and 〈strong〉19b〈/strong〉 exhibited the most potent inhibitory activity toward dihydrotestosterone-induced proliferation of several androgen-dependent cell lines, SC-3 (wild-type AR), LNCaP (T877A AR), and 22Rv1 (H874Y AR), but interestingly also inhibited proliferation of AR-independent PC-3 cells. These compounds, which have a different pharmacophore from conventional AR antagonists, are promising drug candidates for the treatment of prostate cancer.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618313968-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Tsuyoshi Shinozuka, Tomoharu Tsukada, Kunihiko Fujii, Eri Tokumaru, Kousei Shimada, Yoshiyuki Onishi, Yumi Matsui, Satoko Wakimoto, Masanori Kuroha, Tsuneaki Ogata, Kazushi Araki, Jun Ohsumi, Ryoko Sawamura, Nobuaki Watanabe, Hideki Yamamoto, Kazunori Fujimoto, Yoshiro Tani, Makoto Mori, Jun Tanaka〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Attempts were made to reduce the lipophilicity of previously synthesized compound (〈strong〉II〈/strong〉) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency 〈em〉in vitro〈/em〉, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (〈strong〉I〈/strong〉, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction. DS-6930 maintained diminished PPARγ-related adverse effects upon toxicological evaluation 〈em〉in vivo〈/em〉, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clinically in T2DM patients.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618313099-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Kenzo Yamatsugu, Masahiro Furuta, Siqi Xi, Yoshifumi Amamoto, Jiaan Liu, Shigehiro A. Kawashima, Motomu Kanai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Lysine acylation of proteins is a crucial chemical reaction, both as a post-translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents. We, herein, conducted a kinetic analysis of the ability of DSH and several derivatives to mediate lysine acetylation to better understand the structural elements essential for high acetylation activity under physiological conditions. Interestingly, the obtained trend in reactivity was different from that observed in organic solvents, suggesting that a different principle is necessary for designing chemical catalysts specifically for use under physiological conditions compared to catalysts for use in organic solvents. Based on the obtained information, we identified a new catalyst scaffold with high activity and structural flexibility for further modification to improve this catalyst system.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618304243-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Shiyang Zhou, Guangying Chen, Gangliang Huang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. 〈em〉In vitro〈/em〉 experiments showed that compounds 〈strong〉3a〈/strong〉, 〈strong〉3d〈/strong〉 and 〈strong〉3f〈/strong〉 had intensity inhibition the biological activity of MAO-A, while compounds 〈strong〉3i〈/strong〉 and 〈strong〉3m〈/strong〉 had intensity inhibition the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments 〈em〉in vitro〈/em〉, that the compound 〈strong〉3d〈/strong〉 was IC〈sub〉50〈/sub〉 = 3.12 ± 0.05 μmol/mL of MAO-A and compound 〈strong〉3m〈/strong〉 was IC〈sub〉50〈/sub〉 = 5.04 ± 0.06 μmol/mL. 〈em〉In vivo〈/em〉 inhibition activity experiments were conducted to evaluate the inhibitory activity of compounds 〈strong〉3a〈/strong〉, 〈strong〉3d〈/strong〉, 〈strong〉3f, 3i〈/strong〉 and 〈strong〉3m〈/strong〉 by detecting the contents of 5-HT, NE, DA and activity of MAO-A and MAO-B in plasma and brain tissue. 〈em〉In vivo〈/em〉 inhibition activity evaluation results showed that the compounds 〈strong〉3a〈/strong〉, 〈strong〉3d〈/strong〉, 〈strong〉3f〈/strong〉, 〈strong〉3i〈/strong〉 and 〈strong〉3m〈/strong〉 had increased the contents of 5-HT, NE and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in plasma and brain tissue showed that the compounds 〈strong〉3a〈/strong〉, 〈strong〉3d〈/strong〉, and 〈strong〉3f〈/strong〉 had a significant inhibitory effect on the activity of MAO-A, while the compounds 〈strong〉3i〈/strong〉 and 〈strong〉3m〈/strong〉 showed inhibitory effect on the activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618312161-ga1.jpg" width="278" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 21〈/p〉 〈p〉Author(s): Ju-Hyeon Lee, Ashraf K. El-Damasy, Seon Hee Seo, Changdev G. Gadhe, Ae Nim Pae, Nakcheol Jeong, Soon-Sun Hong, Gyochang Keum〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-〈em〉d〈/em〉]pyrimidine octamides (〈strong〉4a〈/strong〉–〈strong〉o〈/strong〉 and 〈strong〉6a〈/strong〉–〈strong〉g〈/strong〉) and their corresponding free amines 〈strong〉5a〈/strong〉–〈strong〉m〈/strong〉 and 〈strong〉7a〈/strong〉–〈strong〉g〈/strong〉 have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 〈strong〉6d〈/strong〉–〈strong〉g〈/strong〉 as well as the amine derivative 〈strong〉7b〈/strong〉 have shown the best anticancer activity with single digit micromolar GI〈sub〉50〈/sub〉 values over the tested cancer cells, and low cytotoxic effects (GI〈sub〉50〈/sub〉 〉 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-〈em〉d〈/em〉]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 〈strong〉6f〈/strong〉 was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI〈sub〉50〈/sub〉 and TGI values over multiple cancer cells. Kinase profile of compound 〈strong〉6f〈/strong〉 over 53 oncogenic kinases at 10 µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 〈strong〉6f〈/strong〉 against TrkA (IC〈sub〉50〈/sub〉 = 2.25 µM), FGFR4 (IC〈sub〉50〈/sub〉 = 6.71 µM) and Tie2 (IC〈sub〉50〈/sub〉 = 6.84 µM) was explained by molecular docking study, which also proposed that 〈strong〉6f〈/strong〉 may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 〈strong〉6f〈/strong〉 may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618307818-ga1.jpg" width="399" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Bonsu Ku, Hye-Yeoung Yun, Kyung Won Lee, Ho-Chul Shin, Sang-Rae Lee, Chang Hyen Kim, Hwangseo Park, Kyu Yang Yi, Chang Hoon Lee, Seung Jun Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Cytosolic protein tyrosine phosphatase epsilon (cyt-PTPε) plays a central role in controlling differentiation and function of osteoclasts, whose overactivation causes osteoporosis. Based on our previous study reporting a number of cyt-PTPε inhibitory chemical compounds, we carried out a further and extended analysis of our compounds to examine their effects on cyt-PTPε-mediated dephosphorylation and on osteoclast organization and differentiation. Among five compounds showing target selectivity to cyt-PTPε over three other phosphatases 〈em〉in vitro〈/em〉, two compounds exhibited an inhibitory effect against the dephosphorylation of cellular Src protein, the cyt-PTPε substrate. Moreover, these two compounds caused destabilization of the podosome structure that is necessary for the bone-resorbing activity of osteoclasts, and also attenuated cellular differentiation of monocytes into osteoclasts, without affecting cell viability. Therefore, these findings not only verified anti-osteoclastic effects of our cyt-PTPε inhibitory compounds, but also showed that cyt-PTPε expressed in osteoclasts could be a putative therapeutic target worth considering.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618313671-ga1.jpg" width="337" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 29 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Kazuma Ogawa, Ryohei Masuda, Kenji Mishiro, Mengfei Wang, Takashi Kozaka, Kazuhiro Shiba, Seigo Kinuya, Akira Odani〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (〈strong〉5〈/strong〉) (K〈sub〉i〈/sub〉 = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 〈strong〉5〈/strong〉. The radioiodine labeled probe [〈sup〉125〈/sup〉I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([〈sup〉125〈/sup〉I]〈strong〉10〈/strong〉) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. Co-injection of [〈sup〉125〈/sup〉I]〈strong〉10〈/strong〉 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉, indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618319989-ga1.jpg" width="414" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 30 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Natarajan Arumugam, Abdulrahman I. Almansour, Raju Suresh Kumar, D. Kotresha, R. Saiswaroop, S. Venketesh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉A small library of new class of dispiropyrrolidinyl-piperidone tethered indono[1,2-〈em〉b〈/em〉]quinoxaline heterocyclic hybrids 7〈strong〉a-j〈/strong〉 were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomenthine ylide employed is first of its kind and generated 〈em〉in situ〈/em〉 from indenoquinoxalinone and 〈em〉L〈/em〉-tryptophan, a combination that has not been employed previously for the 〈em〉in situ〈/em〉 generation of azomethine ylides. The synthesized heterocyclic hybrids 〈strong〉7a-j〈/strong〉 were evaluated for their 〈em〉in vitro〈/em〉 acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, therein compounds 〈strong〉7h〈/strong〉 and 〈strong〉7j〈/strong〉 displayed more potent AChE and BChE enzyme inhibition than the standard drug with IC〈sub〉50〈/sub〉 values of 3.22, 2.01, 12.40 and 10.45 mM, respectively. Molecular docking studies have also been investigated for most active compounds that disclosed interesting binding templates to the active site channel of cholinesterase enzyme.〈/p〉 〈p〉____________________________________________________________________〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619303426-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Shun Nanjyo, Kenji Ohgane, Hiromasa Yoshioka, Makoto Makishima, Yuichi Hashimoto, Tomomi Noguchi-Yachide〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC〈sub〉50〈/sub〉 as a measure of potency, and E〈sub〉max〈/sub〉 as a measure of efficacy.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619302305-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Marcela Martínez-Busi, Florencia Arredondo, David González, Carolina Echeverry, Mauricio A. Vega-Teijido, Diego Carvalho, Alejandra Rodríguez-Haralambides, Felicia Rivera, Federico Dajas, Juan A. Abin-Carriquiry〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉〈em〉Achyrocline satureioides〈/em〉 (Lam) D.C (Compositae) is a native medicinal plant of South America traditionally utilized for its anti-inflammatory, sedative and anti-atherosclerotic properties among others. Neuroprotective effects have been reported in vivo and could be associated to its elevated content of flavonoid aglycones. In the present study we performed the isolation and structure elucidation of the major individual flavonoids of 〈em〉A. satureioides〈/em〉 along with the 〈em〉in vitro〈/em〉 characterization of their individual antioxidant and neuroprotective properties in order to see their putative relevance for treating neurodegeneration.〈/p〉 〈p〉Exact mass, HPLC-MS/MS and 〈sup〉1〈/sup〉H NMR identified dicaffeoyl quinic acid isomers, quercetin, luteolin, isoquercitrin, and 3-O-methylquercetin as the mayor polyphenols. Flavonoids intrinsic redox properties were evaluated in the presence of the endogenous antioxidants GSH and Ascorbate. Density Functional Theory (DFT) molecular modeling and electron density studies showed a theoretical basis for their different redox properties. Finally, 〈em〉in vitro〈/em〉 neuroprotective effect of each isolated flavonoid was evaluated against hydrogen peroxide-induced toxicity in a primary neuronal culture paradigm. Our results showed that quercetin was more efficacious than luteolin and isoquercitrin, while 3-O-methylquercetin was unable to afford neuroprotection significantly. This was in accordance with the susceptibility of each flavonoid to be oxidized and to react with GSH. Overall our results shed light on chemical and molecular mechanisms underlying bioactive actions of 〈em〉A. satureioides〈/em〉 main flavonoids that could contribute to its neuroprotective effects and support the positive association between the consumption of 〈em〉A. satureioides〈/em〉 as a natural dietary source of polyphenols, and beneficial health effect.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619301300-ga1.jpg" width="254" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Genichiro Tsuji, Takayuki Hattori, Masashi Kato, Wataru Hakamata, Hideshi Inoue, Mikihiko Naito, Masaaki Kurihara, Yosuke Demizu, Takuji Shoda〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fluorescence labeling of the target molecules using a small molecule-based probe is superior than a method using genetically expressed green fluorescence protein (GFP) in terms of convenience in its preparation and functionalization. Fluorophore-nitrilotriacetic acid (NTA) conjugates with several ester protecting groups were synthesized and evaluated for their cell membrane permeability by fluorescence microscopy analysis. One of the derivatives, acetoxymethyl (AM)-protected NTA conjugate is hydrolyzed, resulting in intracellular accumulation, thus providing localized fluorescence intensity in cells. This modification is expected as an effective method for converting a non-cell membrane permeable NTA-BODIPY conjugates to a cell membrane permeable derivatives.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618307545-ga1.jpg" width="480" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Laura L. Kiessling〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Carbohydrates are the most prominent features of the cell’s exterior—they are the cell’s “face” and serve as the cell’s identification card. The features of cell surface glycans (e.g. glycoproteins, glycolipids, polysaccharides) can be read by proteins, other cells, or organisms. In all of these contexts, glycan-binding proteins typically recognize (“read”) glycan identity. This recognition mediates important host-microbe interactions, as well as critical physiological functions, including fertilization, development, and immune system function. This article focuses on how proteins recognize glycans with an emphasis on three objectives: 1) to understand the molecular basis for carbohydrate recognition, 2) to implement that understanding to develop functional probes of protein-carbohydrate interactions, and 3) to apply those probes to elucidate and exploit the physiological consequences of protein–carbohydrate interactions. In this context, our group has focused on two key aspects of carbohydrate recognition: CH-π and multivalent interactions. We are applying the foundational knowledge gained from our studies for purposes ranging from illuminating host-microbe interactions to probing immune system function.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Deboshikha Bhattacharjee, Sanjoy Kumar Sheet, Snehadrinarayan Khatua, Koel Biswas, Santaram Joshi, Bekington Myrboh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A library of biologically important heterocycles, viz. pyrazolyl pyrimidine-triones, bis(heterocyclyl)methanes were successfully synthesised by the condensation of barbituric acid, pyrazolone with an aldehyde and dimedone/4-hydoxy coumarin with various substituted aldehydes in aqueous medium at room temperature catalysed by nickel nanoparticles which proved to be an efficient magnetically recyclable catalyst. The method is simple, eco-friendly and gave excellent yields of the products without taking recourse to column chromatographic separation procedures. Computational method was employed to elucidate the selective formation of uncyclised product in reaction course. The biological activity of the synthesized compounds were investigated and the results demonstrated profound antibacterial activity.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618309507-ga1.jpg" width="341" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Frederick M. Tomlin, Chelsea G. Gordon, Yisu Han, Taia S. Wu, Ellen M. Sletten, Carolyn R. Bertozzi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The quadricyclane (QC) ligation is a bioorthogonal reaction between a quadricyclane moiety and a nickel bis(dithiolene) derivative. Here we show that a QC amino acid can be incorporated into a protein site-specifically using the pyrrolysine-based genetic code expansion platform, and subsequently used for ligation chemistry. Additionally, we exploited the photolability of the QC ligation product to render the adduct cleavable with a handheld UV lamp. We further developed a protein purification method that involves QC ligation of biotin to a protein of interest, capture on streptavidin resin, and finally release using only UV light. The QC ligation thus brings novel chemical manipulations to the realm of bioorthogonal chemistry.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089617324537-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 22〈/p〉 〈p〉Author(s): Gang Cheng, Ping Xu, Minkui Zhang, Jing Chen, Rong Sheng, Yongmin Ma〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The 3-hydroxypyran-4-one moiety (maltol) was incorporated into the structure of resveratrol to achieve a series of resveratrol-maltol hybrids (〈strong〉8a〈/strong〉–〈strong〉8k〈/strong〉) as novel multi-target-directed ligands (MTDLs). In vitro biological evaluation of the MTDLs revealed these compounds to have a triple function, namely inhibition of self-induced Aβ〈sub〉1–42〈/sub〉 aggregation, antioxidation, and metal chelating activity. Among all the evaluated MTDLs, compounds 〈strong〉8i〈/strong〉 and 〈strong〉8j〈/strong〉 showed the most promise, demonstrating micromolar IC〈sub〉50〈/sub〉 values for Aβ〈sub〉1–42〈/sub〉 aggregation inhibition, more potent ABTS〈sup〉〈img src="https://sdfestaticassets-eu-west-1.sciencedirectassets.com/shared-assets/16/entities/rad"〉+〈/sup〉 scavenging activity than Trolox, and good metal chelating activities.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618310897-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Binh Huy Le, Thuy-Van Thi Nguyen, Han Na Joo, Young Jun Seo〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Large-Stokes-shift based simple folded DNA probing system (LSFP) had a simple folded DNA structure and exhibited a large Stokes-shifted (194 nm) fluorescence signal upon excitation at a single wavelength (386 nm). This Stokes shift was achieved through a simple combination of donor and acceptor fluorophores and employing multi-FRET systematically. This unique large Stokes-shifted fluorescence signal was used to detect target DNA with large increases in the fluorescence signal (9.7–14.2 fold). This LSFP exhibited enough selectivity, distinguishing a perfectly matched sequence from the probe itself and mismatched sequences. Surprisingly, when DSN was used for signal amplification with 〈strong〉miR21P〈/strong〉 probing system whose target is miRNA 21, it showed high sensitivity (13.7 aM) and selectivity (one base mismatch discrimination). This system has several advantages over other molecular beacons (MBs): (i) it is easy to design and synthesize the probing system that does not require the construction of a finely designed stem and loop, as in most MBs (this can prevent the degradation of 〈strong〉miR21P〈/strong〉 itself by DSN enzyme without special backbone modification); (ii) it can control unique fluorescence, such as large Stokes-shifted fluorescence through a simple combination of donor and acceptor fluorophores; and (iii) through signal amplification using DSN, it can efficiently detect extremely small amounts of target miRNA with high sensitivity (13.7 aM).〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311507-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Michelle E. Boursier, Daniel E. Manson, Joshua B. Combs, Helen E. Blackwell〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Certain bacteria can coordinate group behaviors via a chemical communication system known as quorum sensing (QS). Gram-negative bacteria typically use 〈em〉N〈/em〉-acyl 〈span〉l〈/span〉-homoserine lactone (AHL) signals and their cognate intracellular LuxR-type receptors for QS. The opportunistic pathogen 〈em〉Pseudomonas aeruginosa〈/em〉 has a relatively complex QS circuit in which two of its LuxR-type receptors, LasR and QscR, are activated by the same natural signal, 〈em〉N〈/em〉-(3-oxo)-dodecanoyl 〈span〉l〈/span〉-homoserine lactone. Intriguingly, once active, LasR activates virulence pathways in 〈em〉P. aeruginosa〈/em〉, while activated QscR can inactivate LasR and thus repress virulence. We have a limited understanding of the structural features of AHLs that engender either agonistic activity in both receptors or receptor-selective activity. Compounds with the latter activity profile could prove especially useful tools to tease out the roles of these two receptors in virulence regulation. A small collection of AHL analogs was assembled and screened in cell-based reporter assays for activity in both LasR and QscR. We identified several structural motifs that bias ligand activation towards each of the two receptors. These findings will inform the development of new synthetic ligands for LasR and QscR with improved potencies and selectivities.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618305339-fx1.jpg" width="282" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Manda Sathish, Sabanis Chetan Dushantrao, Shalini Nekkanti, Ramya Tokala, Soujanya Thatikonda, Yellaiah Tangella, Gunda Srinivas, Shirisha Cherukommu, Namballa Hari Krishna, Nagula Shankaraiah, Narayana Nagesh, Ahmed Kamal〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of new C3-〈em〉trans〈/em〉-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC〈sub〉50〈/sub〉 values 13–45 nM. Moreover, the conjugates 〈strong〉8v〈/strong〉 and 〈strong〉8x〈/strong〉 were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618309969-ga1.jpg" width="337" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Lalith K. Kummari, Mark S. Butler, Emily Furlong, Ross Blundell, Amanda Nouwens, Alberto B. Silva, Ulrike Kappler, James A. Fraser, Bostjan Kobe, Matthew A. Cooper, Avril A.B. Robertson〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the 〈em〉de novo〈/em〉 purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against 〈em〉Cryptococcus neoformans〈/em〉 IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[〈em〉b〈/em〉]thiophene 1,1-dioxides that inhibited 〈em〉Cryptococcus〈/em〉 IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar 〈em〉in vitro〈/em〉 activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition 〈em〉in vitro,〈/em〉 but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[〈em〉b〈/em〉]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with 〈em〉Cryptococcus〈/em〉 IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[〈em〉b〈/em〉]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311416-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 December 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issues 23–24〈/p〉 〈p〉Author(s): Junhao Xing, Lingyun Yang, Jinpei Zhou, Huibin Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at 〈em〉P〈/em〉1 and 〈em〉P〈/em〉4 groups led to the discovery of compound 〈strong〉16g〈/strong〉: a highly potent, selective fXa inhibitor with pronounced 〈em〉in vitro〈/em〉 anticoagulant activity. Moreover, 〈strong〉16g〈/strong〉 also displayed excellent 〈em〉in vivo〈/em〉 antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 〈strong〉16g〈/strong〉 had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. Additionally, 〈strong〉16g〈/strong〉 also exhibited satisfactory PK profiles. Eventually, 〈strong〉16g〈/strong〉 was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 〈strong〉16g〈/strong〉.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961830840X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Wenchao Lu, Huan Xiong, Yu Chen, Chen Wang, Hao Zhang, Pan Xu, Jie Han, Senhao Xiao, Hong Ding, Zhifeng Chen, Tian Lu, Jun Wang, Yuanyuan Zhang, Liyan Yue, Yu-Chih Liu, Chenhua Zhang, Yaxi Yang, Hualiang Jiang, Kaixian Chen, Bing Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of ε-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for 〈em〉in vivo〈/em〉 use that underlies the therapeutic potential for p300/CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311465-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Aarajana Shrestha, Seojeong Park, Hae Jin Jang, Pramila Katila, Ritina Shrestha, Youngjoo Kwon, Eung-Seok Lee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉DNA Topoisomerase IIα (topo IIα) is one of the most effective therapeutic targets to control cancer. In an effort to develop novel and effective topo IIα targeting anti-proliferative agent, a phenolic series of indenopyridinone and indenopyridinol were designed and prepared using efficient multi-component one pot synthetic method. Total twenty-two synthesized compounds were assessed for topo I and IIα inhibition, and anti-proliferation in three different human cancer cell lines. Overall structure-activity relationship study explored the significance of 〈em〉meta-〈/em〉phenolic group at 4-position and 〈em〉para-〈/em〉phenolic group at 2- and/or 4-position of indenopyridinone skeleton for strong topo IIα-selective inhibition and anti-proliferative activity against human cervix (HeLa) and colorectal (HCT15) cell lines. Compound 〈strong〉12〈/strong〉 with excellent topo IIα inhibition (93.7%) was confirmed as a DNA intercalator that could be a new promising lead to develop effective topo IIα-targeted anticancer agents.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961831513X-ga1.jpg" width="481" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Tejosmita Sen, Kashmiri Neog, Sangita Sarma, Prasenjit Manna, Hari Prasanna Deka Boruah, Pranjal Gogoi, Anil Kumar Singh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉Mycobacterium tuberculosis〈/em〉 infection causes 1.8 million deaths worldwide, of which half a million has been diagnosed with resistant tuberculosis (TB). Emergence of multi drug resistant and extensive drug resistant strains has made all the existing anti-TB therapy futile. The major involvement of efflux pump in drug resistance has made it a direct approach for therapeutic exploration against resistant 〈em〉M. tuberculosis〈/em〉. This study demarcates the role of 11H-pyrido[2,1-b]quinazolin-11-one (quinazolinone) analogues as efflux pump inhibitor in 〈em〉Mycobacterium smegmatis〈/em〉. Sixteen quinazolinone analogues were synthesized by treating 2-aminopyridine and 2-fluorobenzonitrile with K〈em〉〈sup〉t〈/sup〉〈/em〉OBu. Analogues were tested, and 〈strong〉3a〈/strong〉, 〈strong〉3b〈/strong〉, 〈strong〉3c〈/strong〉, 〈strong〉3g〈/strong〉, 〈strong〉3j〈/strong〉, 〈strong〉3l〈/strong〉, 〈strong〉3m〈/strong〉, and 〈strong〉3p〈/strong〉 were found to modulate EtBr MIC by 〉4 whereas 〈strong〉3a〈/strong〉, 〈strong〉3g〈/strong〉, 〈strong〉3i〈/strong〉 and 〈strong〉3o〈/strong〉 showed 〉4 modulation on norfloxacin MIC. 〈strong〉3l〈/strong〉 and 〈strong〉3o〈/strong〉 in addition to their very low toxicity they showed high EtBr and norfloxacin accumulation respectively. Time kill curve showed effective log reduction in colony forming unit in presence of these analogues, thus confirming their role as efflux pump inhibitor. Through docking and alignment studies, we have also shown that the LfrA amino acid residues that the analogues are interacting with are present in Rv2333c and Rv2846c of 〈em〉M. tuberculosis〈/em〉. This study have shown for the first time the possibility of developing the 11H-pyrido[2,1-b]quinazolin-11-one analogues as efflux pump inhibitors for 〈em〉M. smegmatis〈/em〉 and hence unbolts the scope to advance this study against resistant 〈em〉M. tuberculosis〈/em〉 as well.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618312781-ga1.jpg" width="155" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Shao-Ru Chen, Feng Li, Mo-Yu Ding, Decai Wang, Qi Zhao, Yitao Wang, Guo-Chun Zhou, Ying Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Sustained activation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway contributed to the progression of cancer and liver diseases. STAT3 signaling inhibitor has been extensively investigated for pharmacological use. We synthesized a series of andrographolide derivatives, and characterized their activity against STAT3 signaling pathway both in vitro and in the CCl〈sub〉4〈/sub〉-induced acute liver damage mice model. Among these derivatives, compound 〈strong〉24〈/strong〉 effectively inhibited phosphorylation and dimerization of STAT3 but not its DNA binding activity. Compound 〈strong〉24〈/strong〉 significantly ameliorated carbon tetrachloride-induced acute liver damage 〈em〉in vivo〈/em〉 without changing mice body weight. Treatment with 〈strong〉24〈/strong〉 attenuated hepatic pathologic damage and promoted hepatic proliferation and activation of STAT3. Compound 〈strong〉24〈/strong〉 inhibited elevated expression of α-smooth muscle actin and serum pro-inflammatory cytokines downstream of STAT3 but not those factors that are regulated by NF-κB or SMADs. In summary, our results suggest that compound 〈strong〉24〈/strong〉 may serve as a potential therapeutic agent for the treatment of hepatic damage or a liver protection agent via regulating STAT3 activation.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618308800-ga1.jpg" width="251" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Tom Baladi, Jessy Aziz, Florent Dufour, Valentina Abet, Véronique Stoven, François Radvanyi, Florent Poyer, Ting-Di Wu, Jean-Luc Guerquin-Kern, Isabelle Bernard-Pierrot, Sergio Marco Garrido, Sandrine Piguel〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The TAM kinase family arises as a new effective and attractive therapeutic target for cancer therapy, autoimmune and viral diseases. A series of 2,6-disubstituted imidazo[4,5-〈em〉b〈/em〉]pyridines were designed, synthesized and identified as highly potent TAM inhibitors. Despite remarkable structural similarities within the TAM family, compounds 〈strong〉28〈/strong〉 and 〈strong〉25〈/strong〉 demonstrated high activity and selectivity 〈em〉in vitro〈/em〉 against AXL and MER, with IC〈sub〉50〈/sub〉 value of 0.77 nM and 9 nM respectively and a 120- to 900-fold selectivity. We also observed an unexpected nuclear localization for compound 〈strong〉10Bb〈/strong〉, thanks to nanoSIMS technology, which could be correlated to the absence of cytotoxicity on three different cancer cell lines being sensitive to TAM inhibition.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618313804-ga1.jpg" width="488" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Sateesh Kumar Arepalli, Chaerim Lee, Seongrak Sim, Kiho Lee, Hyunji Jo, Kyu-Yeon Jun, Youngjoo Kwon, Jong-Soon Kang, Jae-Kyung Jung, Heesoon Lee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A novel series of 35 angularly fused pentacyclic 13〈em〉H〈/em〉-benzo[〈em〉f〈/em〉]chromeno[4,3-〈em〉b〈/em〉][1,7]naphthyridines and 13〈em〉H〈/em〉-benzo[〈em〉f〈/em〉]chromeno[4,3-〈em〉b〈/em〉][1,7]naphthyridin-5-ium chlorides were designed and synthesized. Their cytotoxic activities were investigated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Among all screened compounds; 〈strong〉28〈/strong〉, 〈strong〉30〈/strong〉, 〈strong〉34〈/strong〉, 〈strong〉35〈/strong〉, 〈strong〉46〈/strong〉, 〈strong〉48〈/strong〉, 〈strong〉52〈/strong〉, and 〈strong〉53〈/strong〉 compounds exhibited potent cytotoxic activities against all tested human cancer cell lines. Further, these potent lead cytotoxic agents were evaluated against human Topoisomerase I and IIα inhibition. Among them, the compound 〈strong〉48〈/strong〉 exhibited dual Topoisomerase I and IIα inhibition especially at 20 μM concentrations the compound 〈strong〉48〈/strong〉 exhibited 1.25 times more potent Topoisomerase IIα inhibitory activity (38.3%) than the reference drug etoposide (30.6%). The compound 〈strong〉52〈/strong〉 also exhibited excellent (88.4%) topoisomerase I inhibition than the reference drug camptothecin (66.7%) at 100 μM concentrations. Molecular docking studies of the compounds 〈strong〉48〈/strong〉 and 〈strong〉52〈/strong〉 with topo I discovered that they both intercalated into the DNA single-strand cleavage site where the compound 〈strong〉48〈/strong〉 have van der Waals interactions with residues Arg364, Pro431, and Asn722 whilst the compound 〈strong〉52〈/strong〉 have with Arg364, Thr718, and Asn722 residues. Both the compounds 〈strong〉48〈/strong〉 and 〈strong〉52〈/strong〉 have π–π stacking interactions with the stacked DNA bases. The docking studies of the compound 〈strong〉48〈/strong〉 with topo IIα explored that it was bound to the topo IIα DNA cleavage site where etoposide was situated. The benzo[〈em〉f〈/em〉]chromeno[4,3-〈em〉b〈/em〉][1,7]naphthyridine ring of the compound 〈strong〉48〈/strong〉 was stacked between the DNA bases of the cleavage site with π–π stacking interactions and there were no hydrogen bond interactions with topo IIα.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618312914-ga1.jpg" width="251" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Lara A. Zimmermann, Milene H. de Moraes, Rafael da Rosa, Eduardo B. de Melo, Fávero R. Paula, Eloir P. Schenkel, Mario Steindel, Lílian S.C. Bernardes〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against 〈em〉Trypanosoma cruzi〈/em〉 amastigotes. Thirty-seven compounds were active, and eight of them had GI〈sub〉50〈/sub〉 values lower than 100 μM (GI〈sub〉50〈/sub〉 88.4–12.2 μM). A qualitative structure activity relationship study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compounds. Compound 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole (〈strong〉31〈/strong〉) was the most active in the series (GI〈sub〉50〈/sub〉 12.2 μM), showing, 〈em〉in vitro,〈/em〉 low toxicity and potency similar to benznidazole (GI〈sub〉50〈/sub〉 10.2 μM). These results suggest that this compound can be a promising scaffold for the design of new trypanocidal compounds.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311672-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Cristina Y. Zamora, Amaël G.E. Madec, Wilma Neumann, Elizabeth M. Nolan, Barbara Imperiali〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The human enteropathogen 〈em〉Campylobacter jejuni〈/em〉, like many bacteria, employs siderophores such as enterobactin for cellular uptake of ferric iron. This transport process has been shown to be essential for virulence and presents an attractive opportunity for further study of the permissiveness of this pathway to small-molecule intervention and as inspiration for the development of synthetic carriers that may effectively transport cargo into Gram-negative bacteria. In this work, we have developed a facile and robust microscale assay to measure growth recovery of 〈em〉C. jejuni〈/em〉 NCTC 11168 in liquid culture as a result of ferric iron uptake. In parallel, we have established the solid-phase synthesis of catecholamide compounds modeled on enterobactin fragments. Applying these methodological developments, we show that small synthetic iron chelators of minimal dimensions provide ferric iron to 〈em〉C. jejuni〈/em〉 with equal or greater efficiency than enterobactin.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961830484X-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Michael S. Malamas, Jimit Girish Raghav, Xiaoyu Ma, Chandrashekhar Honrao, JodiAnne T. Wood, Othman Benchama, Han Zhou, Srikrishnan Mallipeddi, Alexandros Makriyannis〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉New oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of Δ〈sup〉8〈/sup〉-THC. The scope of the research was to drastically alter two important physicochemical properties hydrophobicity (log P) and topological surface area (tPSA) of the compound, which play a critical role in tissue distribution and sequestration (depot effect). Key synthesized analogs demonstrated sub-nanomolar affinity for CB1, marked reduction in hydrophobicity (ClogP∼2.5–3.5 vs 9.09 of Δ〈sup〉8〈/sup〉-THC-DMH), and found to function as either agonists (〈em〉trans〈/em〉-oximes) or neutral antagonists (〈em〉cis〈/em〉-oximes) in a cAMP functional assay. All oxime analogs showed comparable affinity at the CB2 receptor, but surprisingly they were found to function as inverse agonists for CB2. In behavioral studies (i.e. analgesia, hypothermia) 〈em〉trans〈/em〉-oxime 〈strong〉8a〈/strong〉 exhibited a predictable fast onset (∼20 min) and short duration of pharmacological action (∼180 min), in contrast to the very prolonged duration of Δ〈sup〉8〈/sup〉-THC-DMH (〉24 h), thus limiting the potential for severe psychotropic side-effects associated with persistent activation of the CB1 receptor. We have conducted 100 ns molecular dynamic (MD) simulations of CB1 complexes with AM11542 (CB1 agonist) and both 〈em〉trans〈/em〉-〈strong〉8a〈/strong〉 and 〈em〉cis〈/em〉-〈strong〉8b〈/strong〉 isomeric oximes. These studies revealed that the C3 alkyl tail of 〈em〉cis〈/em〉-〈strong〉8b〈/strong〉 orientated within the CB1 binding pocket in a manner that triggered a conformational change that stabilized the CB1 receptor at its inactive-state (antagonistic functional effect). In contrast, the 〈em〉trans〈/em〉-〈strong〉8a〈/strong〉 isomer’s conformation was coincided with that of the AM11542 CB1 agonist-bound structure, stabilizing the CB1 receptor at the active-state (agonistic functional effect). We have selected oxime 〈em〉trans〈/em〉-〈strong〉8a〈/strong〉 based on its potency for CB1, and favorable pharmacodynamic profile, such as fast onset and predictable duration of pharmacological action, for evaluation in pre-clinical models of anorexia nervosa.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311076-ga1.jpg" width="338" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Luke Taylor, Nick Krueger, Olga Malysheva, Jeffrey Atkinson, Robert S. Parker〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉α-Tocopherol (α-TOH) is the primary lipophilic radical trapping antioxidant in human tissues. Oxidative catabolism of α-tocopherol (αTOH) is initiated by ω-hydroxylation of the terminal carbon (C-13) of the isoprenoid sidechain followed by oxidative transformations that sequentially truncate the chain to yield the 2,5,7,8-tetramethyl(3′carboxyethyl)-6-hydroxychroman (α-CEHC). After conjugation to glucuronic acid, 3′-carboxyethyl-6-hydroxychroman glucuronide is excreted in urine. We report here that the same enzyme that accomplishes this task, the cytochrome P450 monooxygenase CYP-4F2, can also ω-hydroxylate the terminal carbon of α-tocopheryl quinone. A standard sample of ω-OH-α-tocopheryl quinone (ω-OH-α-TQ) was synthesized as a mixture of stereoisomers by allylic oxidation of α-tocotrienol using SeO〈sub〉2〈/sub〉 followed by double-bond reduction and oxidation to the quinone. After incubating human liver microsomes or insect cell microsomes expressing only recombinant human CYP-4F2, cytochrome b5, and NADPH P450 reductase with 〈em〉d〈/em〉〈sub〉6〈/sub〉-α-tocopheryl quinone (〈em〉d〈/em〉〈sub〉6〈/sub〉-αTQ), we showed that the ω-hydroxylated (13-OH) d〈sub〉6〈/sub〉-α-TQ was produced. We further identified the production of the terminal carboxylic acid 〈em〉d〈/em〉〈sub〉6〈/sub〉-13-COOH-αTQ. The ramifications of this discovery to the understanding of tocopherol utilization and metabolism, including the quantitative importance of the αTQ-ω-hydroxylase pathway in humans, are discussed.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618315037-ga1.jpg" width="464" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Napon Nilchan, Wanida Phetsang, Taechin Nowwarat, Soraya Chaturongakul, Chutima Jiarpinitnun〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Incorporation of halogen atoms to drug molecule has been shown to improve its properties such as enhanced in membrane permeability and increased hydrophobic interactions to its target. To investigate the effect of halogen substitutions on the antibacterial activity of trimethoprim (TMP), we synthesized a series of halogen substituted TMP and tested for their antibacterial activities against global predominant methicillin resistant 〈em〉Staphylococcus aureus〈/em〉 (MRSA) strains. Structure-activity relationship analysis suggested a trend in potency that correlated with the ability of the halogen atom to facilitate in hydrophobic interaction to saDHFR. The most potent derivative, iodinated trimethoprim (TMP-I), inhibited pathogenic bacterial growth with MIC as low as 1.25 μg/mL while the clinically used TMP derivative, diaveridine, showed resistance. Similar to TMP, synergistic studies indicated that TMP-I functioned synergistically with sulfamethoxazole. The simplicity in the synthesis from an inexpensive starting material, vanillin, highlighted the potential of TMP-I as antibacterial agent for MRSA infections.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618304231-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Rita Fuerst, Jun Yong Choi, Anna M. Knapinska, Lyndsay Smith, Michael D. Cameron, Claudia Ruiz, Gregg B. Fields, William R. Roush〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A structure-activity/structure-property relationship study based on the physicochemical as well as 〈em〉in vitro〈/em〉 pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (〈strong〉2〈/strong〉) was undertaken. After systematic variation of inhibitor 〈strong〉2〈/strong〉, compound 〈strong〉31〈/strong〉 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 μM, and a permeability coefficient greater than 20 × 10〈sup〉−6〈/sup〉 cm/s. Compound 〈strong〉31〈/strong〉 also showed excellent 〈em〉in vivo〈/em〉 PK properties after IV dosing (C〈sub〉max〈/sub〉 = 56.8 μM, T〈sub〉1/2〈/sub〉 (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for 〈em〉in vivo〈/em〉 efficacy studies in an OA animal model.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618310186-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Rui Yang, Yu Chen, Liangkun Pan, Yanyan Yang, Qiang Zheng, Yue Hu, Yuxi Wang, Liangren Zhang, Yang Sun, Zhongjun Li, Xiangbao Meng〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for cancer immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline-5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant inhibition potency and high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). The structure-activity relationship was also summarized. The most potent compounds 〈strong〉5c〈/strong〉 (IC〈sub〉50〈/sub〉 23 nM, IDO1 enzyme), and 〈strong〉5b′〈/strong〉 (IC〈sub〉50〈/sub〉 372 nM, HeLa cell) were identified as promising lead compounds.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618307569-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Simon Ng, Nicholas James Bennett, Jessica Schulze, Nan Gao, Christoph Rademacher, Ratmir Derda〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We have employed genetically-encoded fragment-based discovery to identify novel glycopeptides with affinity for the dendritic cell receptor DC-SIGN. Starting from libraries of 10〈sup〉8〈/sup〉 mannose-conjugated peptides, we identified glycopeptides that exhibited up to a 650-fold increase in multivalent binding affinity for DC-SIGN, which is also preserved in cells. Monovalently, our most potent glycopeptides have a similar potency to a Man〈sub〉3〈/sub〉 oligosaccharide, representing a 15-fold increase in activity compared to mannose. These compounds represent the first examples of glycopeptide ligands that target the CRD of DC-SIGN. The natural framework of glycopeptide conjugates and the simplicity of orthogonal conjugation to make these glycopeptides anticipates a promising future for development of DC-SIGN-targeting moieties.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618303973-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Jiangbo Wang, Robert A. Mook, Xiu-rong Ren, Qingfu Zhang, Genevieve Jing, Min Lu, Ivan Spasojevic, H. Kim Lyerly, David Hsu, Wei Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. Since the discovery of Niclosamide’s anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[〈em〉d〈/em〉]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311386-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Kazuki Ueda, Yuji Okado, Kengo Shigetomi, Makoto Ubukata〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉(+)-Epogymnolactam (〈strong〉1〈/strong〉) was discovered as a novel autophagy inducer from a culture of 〈em〉Gymnopus〈/em〉 sp. in our laboratory. To determine structure-activity relationships among (+)-epogymnolactam analogues comparing with cerulenin (〈strong〉2〈/strong〉), we synthesized 5 analogues including (−)-epogymnolactam (〈strong〉3〈/strong〉) having each different functional group, and 3 analogues with different side-chain lengths. Five analogues, 〈strong〉3〈/strong〉, 〈strong〉4〈/strong〉, 〈strong〉5〈/strong〉, 〈strong〉6〈/strong〉, and 〈strong〉7〈/strong〉 did not significantly increase the ratio of LC3-II to LC3-I as an autophagy marker in NIH3T3 cells. These results suggest that presence and stereochemistry of (2〈em〉R〈/em〉,3〈em〉S〈/em〉)-epoxy group and cyclic 〈em〉syn〈/em〉-form (〈strong〉1b〈/strong〉) of 〈strong〉1〈/strong〉 are important for the activity as autophagy inducer. Hexyl analogue (〈strong〉8〈/strong〉) as well as 〈strong〉1〈/strong〉 having butyl side-chain dose-dependently increased the ratio of LC3-II to LC3-I, whereas octyl analogue (〈strong〉9〈/strong〉) and 〈strong〉2〈/strong〉 rather decreased the ratio. Decyl analogue (〈strong〉10〈/strong〉) did not give a change in the ratio. Although 〈strong〉8〈/strong〉 seemed to be an excellent autophagy inducer, it dose-dependently increased SQSTM1 (p62) as in the case of 〈strong〉2〈/strong〉, whereas 〈strong〉1〈/strong〉 showed a slight dose-dependent decrease of p62 as an index of autophagic protein degradation. These observations suggest that 〈strong〉8〈/strong〉 is an autophagy modulator with different molecular target from 〈strong〉1〈/strong〉 or 〈strong〉2〈/strong〉.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311805-ga1.jpg" width="425" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Minhang Xin, Liandi Zhang, Chongxing Tu, Feng Tang, Jun Wen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of novel hedgehog signaling pathway inhibitors have been designed and synthesized based on our previously reported scaffold of 4-(2-pyrimidinylamino)benzamide. The Hh signaling pathway inhibitory activities were evaluated by Gli-luciferase reporter method and most compounds showed more potent inhibitory activities than vismodegib. Three compounds were picked out to evaluated in vivo for their PK properties, and compound 〈strong〉23b〈/strong〉 bearing a 2-pyridyl A-ring and (morpholin-4-yl)methylene at 3-position of D-ring demonstrated satisfactory PK properties. This study suggested the 4-(2-pyrimidinylamino)benzamides were a series of potent Hh signaling pathway inhibitors, deserving to further structural optimization.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311210-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Yuan Yin, Cheng-Juan Chen, Ru-Nan Yu, Zhi-Jian Wang, Tian-Tai Zhang, Da-Yong Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1〈em〉H〈/em〉-pyrazolo[3,4-〈em〉d〈/em〉]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 〈strong〉12a〈/strong〉, which exhibited potent JAK3 inhibitory activity (IC〈sub〉50〈/sub〉 of 6.2 nM) as well as excellent JAK kinase selectivity (〉60-fold). In cellular assay, 〈strong〉12a〈/strong〉 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC〈sub〉50〈/sub〉 of 9.4 μM). Further, compound 〈strong〉12a〈/strong〉 showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618301470-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Elizabeth H. Kelley, Timothy F. Jamison〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Synthesis of the fused tetrahydrofuran motif comprising the 〈em〉ABC〈/em〉 rings of the marine ladder polyethers tamulamides A and B has been achieved via two different polyepoxide cascade strategies. Investigations into a triepoxide cascade under aqueous conditions revealed the importance of the electronic nature of the cascade end-group with this initial approach. Ultimately, a diepoxide cascade under basic conditions proved most successful, providing the 〈em〉ABC〈/em〉 tetrahydropyran triad in 41% yield.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618304310-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): T.A. Cornell, B.P. Orner〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Methods for the generation of nanoparticles encapsulated within cage proteins, such as ferritins, provide particles with low polydispersities due to size constraint by the cage. The proteins can provide enhanced water solubility to enable biological applications and affinity and identification tags to facilitate delivery or the assembly of advanced materials. Many effective methods have been developed, however, they are often impeded by cage protein instability in the presence of reagents or conditions for formation of the nanoparticles. Although the stability of ferritin cage quaternary structure can be enhanced, application of ferritins to materials science remains limited by unpredictable behaviour. Recently, we reported a medium throughput technique to directly detect the ferritin cage state. Herein, we expand this strategy to screen conditions commonly used for the formation of gold nanoparticles. Not only do we report nanoparticle formation conditions that permit ferritin stability, we establish a general screening strategy based on protein cage stability that could be applied to other protein cages or for the generation of other types of particles.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089617323416-fx1.jpg" width="261" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Giacomo Mari, Simona Catalani, Elena Antonini, Lucia De Crescentini, Fabio Mantellini, Stefania Santeusanio, Paolo Lombardi, Antonella Amicucci, Serafina Battistelli, Serena Benedetti, Francesco Palma〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Tetrahydroberberine (THB), otherwise known as canadine, is a natural alkaloid showing significant pharmacological properties and antioxidant protection against oxidative damage. Herein, we synthetized structurally complex THB analogues, namely pyrrolino-tetrahydroberberines (PTHBs) 〈strong〉4a–g〈/strong〉, containing the pyrrolino[2,3〈em〉-b〈/em〉]pyridine system, by means of the reactions of 1,2-diaza-1,3-dienes and 7,8-dihydroberberine. Aim of the study was to explore the in vitro antioxidant properties of PTHBs in comparison to THB thus to identify the most effective against free radical-induced oxidative injury, by using three different antioxidant tests: the ORAC method, the DNA nicking assay, and the DCFH-DA cellular assay. As a result, PTHB 〈strong〉4d〈/strong〉 emerged among the other THB analogues by exhibiting the best antioxidant properties. First, it was the only compound having an ORAC value completely comparable to that of THB, indicating the same ability to neutralize peroxyl radicals. Secondly, 〈strong〉4d〈/strong〉 showed an even better antioxidant capacity than THB in protecting DNA against ferrous ion-induced strand breaks. These observations were also confirmed in NCTC-2544 human keratinocytes exposed to hydrogen peroxide. Indeed, 〈strong〉4d〈/strong〉 protected cells against oxidation more efficiently than THB both in the short (1 and 3 h) and long (24 h) period of incubation, possibly suggesting increased cell membrane permeability and/or intracellular stability of 〈strong〉4d〈/strong〉 as compared to THB.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311817-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Maddie R. Lemieux, Shajila Siricilla, Katsuhiko Mitachi, Shakiba Eslamimehr, Yuehong Wang, Dong Yang, Jeffrey D. Pressly, Ying Kong, Frank Park, Scott G. Franzblau, Michio Kurosu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of 〈em〉Mycobacterium tuberculosis〈/em〉 (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (〈strong〉1〈/strong〉) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2× MIC concentrations. Pharmacokinetic studies indicate that 〈strong〉1〈/strong〉 has an oral bioavailability with an average 〈em〉F〈/em〉-value of 27.6%. Pleuromutilin may have the potential to be developed into an orally administered anti-TB drug.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618309635-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Erik Stempel, Robert Franz-Xaver Kaml, Nediljko Budisa, Markus Kalesse〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid β-(1-azulenyl)-〈span〉l〈/span〉 alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal. This might be especially useful for cell localization studies and visualizing the targeted proteins. In particular, the synthesis of β-(1-azulenyl)-〈span〉l〈/span〉 alanine was achieved through a Negishi coupling which proved to be a powerful tool for the synthesis of unnatural tryptophan analogs. Upon β-(1-azulenyl)-〈span〉l〈/span〉 alanine incorporation into argyrin C, deep blue octapeptide variant was spectrally and structurally characterized.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618304358-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Yang Gao, Peng Zhang, Anfeng Cui, De-Yong Ye, Meng Xiang, Yong Chu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Glycogen synthase kinase-3β (GSK-3β) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3β inhibitors. Kinetic analysis revealed two typical compounds 〈strong〉6j〈/strong〉 and 〈strong〉3j〈/strong〉 showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3β, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The 〈em〉in vivo〈/em〉 results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1β and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3β, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3β and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618306977-ga1.jpg" width="248" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Abdullah-Al Masum, Kenta Yokoi, Yosuke Hisamatsu, Kana Naito, Babita Shashni, Shin Aoki〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Tumor necrosis factor related apoptosis inducing ligand (TRAIL) triggers the cell-extrinsic apoptosis pathway by complexation with its signaling receptors such as death receptors (DR4 and DR5). TRAIL is a 〈em〉C〈sub〉3〈/sub〉〈/em〉-symmetric type II transmembrane protein, consists of three monomeric units. Cyclometalated iridium(III) complexes such as 〈em〉fac〈/em〉-Ir(tpy)〈sub〉3〈/sub〉 (tpy = 2-(4-tolyl)pyridine) also possess a 〈em〉C〈sub〉3〈/sub〉〈/em〉-symmetric structure and are known to have excellent luminescence properties. In this study, we report on the design and synthesis of a 〈em〉C〈sub〉3〈/sub〉〈/em〉-symmetric and luminescent Ir complex-peptide hybrid (IPH), which contains a cyclic peptide that had been reported to bind to death receptor (DR5). The results of MTT assay of Jurkat, K562 and Molt-4 cells with IPH and co-staining experiments with IPH and an anti-DR5 antibody indicate that IPH binds to DR5 and induces apoptosis in a manner parallel to the DR5 expression level. Mechanistic studies of cell death suggest that apoptosis and necrosis-like cell death are differentiated by the position of the hydrophilic part that connects Ir complex and the peptide units. These findings suggest that IPHs could be a promising tool for controlling apoptosis and necrosis by activation of the extra-and intracellular cell death pathway and to develop new anticancer drugs that detect cancer cells and induce their cell death.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618309040-ga1.jpg" width="206" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Andrew P. Hinck〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The increasing availability of detailed structural information on many biological systems provides an avenue for manipulation of these structures, either for probing mechanism or for developing novel therapeutic agents for treating disease. This has been accompanied by the advent of several powerful new methods, such as the ability to incorporate non-natural amino acids or perform fragment screening, increasing the capacity to leverage this new structural information to aid in these pursuits. The abundance of structural information also provides new opportunities for protein engineering, which may become more and more relevant as treatment of diseases using gene therapy approaches become increasingly common. This is illustrated by example with the TGF-β family of proteins, for which there is ample structural information, yet no approved inhibitors for treating diseases, such as cancer and fibrosis that are promoted by excessive TGF-β signaling. The results presented demonstrate that through several relatively simple modifications, primarily involving the removal of an α-helix and replacement of it with a flexible loop, it is possible to alter TGF-βs from being potent signaling proteins into inhibitors of TGF-β signaling. The engineered TGF-βs have improved specificity relative to kinase inhibitors and a much smaller size compared to monoclonal antibodies, and thus may prove successful as either as an injected therapeutic or as a gene therapy-based therapeutic, where other classes of inhibitors have failed.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618305364-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Tania Luthra, K. Naga Lalitha, A. Uma, Subhabrata Sen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Diabetes a non-communicable disease occurs either due to the lack of insulin or the inability of the human body to recognize it. The recent data indicated an increase in the trend of people diagnosed with type 2 diabetes mainly due to unhealthy life style. Here in we report a new class of oxindole derivatives 〈strong〉6a〈/strong〉-〈strong〉k〈/strong〉〈em〉via〈/em〉 scaffold hopping of known α-glucosidase inhibitors 〈strong〉1〈/strong〉–〈strong〉4〈/strong〉. When molecular docking was performed against a homology model of α-glucosidase the resulting compound 〈strong〉6d〈/strong〉 revealed binding interactions comparable to 〈strong〉1〈/strong〉–〈strong〉4〈/strong〉. The compounds were accessed through a unique condensation-ring opening protocol of pyridofuranone building blocks. Overall the compounds exhibited decent binding to the yeast α-glucosidase, where the most potent compound 〈strong〉6h〈/strong〉, inhibited the enzyme with IC〈sub〉50〈/sub〉 of 0.6 µM. This was nearly threefold improvement from the original known compounds 〈strong〉1〈/strong〉–〈strong〉4〈/strong〉, selected to design the newer analogs. The reaction kinetics of 〈strong〉6h〈/strong〉 indicated competitive inhibition.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618308472-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Jürgen Vahter, Kaido Viht, Asko Uri, Ganesh babu Manoharan, Erki Enkvist〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A previously disclosed protein kinase (PK) CK2-selective inhibitor 4-(2-amino-1,3-thiazol-5-yl)benzoic acid (ATB) and its selenium-containing counterpart (ASB) revealed remarkable room temperature phosphorescence when bound to the ATP pocket of the protein kinase CK2. Conjugation of these fragments with a mimic of CK2 substrate peptide resulted in bisubstrate inhibitors with increased affinity towards the kinase. Attachment of the fluorescent acceptor dye 5-TAMRA to the conjugates led to significant enhancement of intensity of long-lifetime (microsecond-scale) photoluminescence of both sulfur- and selenium-containing compounds. The developed photoluminescent probes make possible selective determination of the concentration of CK2 in cell lysates and characterization of CK2 inhibitors by means of time-gated measurement of photoluminescence.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311350-ga1.jpg" width="426" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Renshuai Liu, Lulu Liu, Tingting Liu, Xinying Yang, Yichao Wan, Hao Fang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Anti-apoptotic Bcl-2 family proteins are vital for cancer cells to escape apoptosis, which make them attractive targets for cancer therapy. Recently, a lead compound 〈strong〉1〈/strong〉 was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with a 〈em〉K〈sub〉i〈/sub〉〈/em〉 value of 5.2 µM. Based on this, a series of substituted tyrosine derivatives were developed and tested for their binding affinities to Bcl-2 protein. Results indicated that these compounds exhibited potent binding affinities to Bcl-2 and Mcl-1 protein but not to Bcl-X〈sub〉L〈/sub〉 protein. Promisingly, compound 〈strong〉6i〈/strong〉 inhibited the binding of BH3 peptide to Bcl-2 and Mcl-1 protein with a 〈em〉K〈sub〉i〈/sub〉〈/em〉 value of 450 and 190 nM respectively, and showed obvious anti-proliferative activities against tested cancer cells.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618311477-ga1.jpg" width="462" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 18〈/p〉 〈p〉Author(s): Chao Ma, Ke Du, Ying Zhao, Linkui Zhang, Baichun Hu, Maosheng Cheng〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Cadmium (Cd) is a potent toxic heavy metal, some studies showed that Cd-induced apoptosis is through ER stress pathway. Compounds of pyrrolo[2,1–c][1,4]benzodiazepine (PBD)-3,11-diones were discovered as potent neuroprotective agents against Cd-induced toxicity in SH-SY5Y cells for the first time. In this study, twenty-six PBD-3,11-dione derivatives were synthesized and evaluated for their neuroprotective activity against Cd-induced toxicity by CCK-8 assay. Their preliminary SARs studies indicated that various substituents were tolerated on the benzene ring, and alkyl heterocycles groups at the N10-position of the PBD-3,11-dione scaffold were important for the activities. Among them, compound 〈strong〉13c〈/strong〉 exhibited the best activity (cell viability = 68.6%, 25 μM). Furthermore, we found that the compound 〈strong〉13c〈/strong〉 could inhibit cadmium-induced cell apoptosis with the downregulation of the ER stress markers GRP78, CHOP, cleaved-caspase12 and cleaved-caspase3 through western blotting. The results of 〈em〉in silico〈/em〉 evaluation of ADME/T properties showed that 〈strong〉13c〈/strong〉 exhibited medium BBB penetration level and promising toxicity profiles. These results proved the potential of 〈strong〉13c〈/strong〉 as a promising lead compound against Cd-induced neurotoxicity.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618312835-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 20〈/p〉 〈p〉Author(s): Ana Daura Travassos de Oliveira Moraes, Mirelly Dianne Santos de Miranda, Íris Trindade Tenório Jacob, Cézar Augusto da Cruz Amorim, Ricardo Olímpio de Moura, Simone Ângela Soares da Silva, Milena Botelho Pereira Soares, Sinara Mônica Vitalino de Almeida, Túlio Ricardo Couto de Lima Souza, Jamerson Ferreira de Oliveira, Teresinha Gonçalves da Silva, Cristiane Moutinho Lagos de Melo, Diogo Rodrigo Magalhães Moreira, Maria do Carmo Alves de Lima〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The objective of this work was to obtain and evaluate anti-inflammatory 〈em〉in vitro, in vivo〈/em〉 and 〈em〉in silico〈/em〉 potential of novel indole-〈em〉N〈/em〉-acylhydrazone derivatives. In total, 10 new compounds (〈strong〉3a〈/strong〉–〈strong〉j〈/strong〉) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 〈strong〉3a〈/strong〉 and 〈strong〉3b〈/strong〉 showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 〈strong〉3b〈/strong〉 induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 〈strong〉3b〈/strong〉 is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 〈strong〉3a〈/strong〉 not presented selectivity towards COX-2. The molecular docking results suggest compounds 〈strong〉3a〈/strong〉 and 〈strong〉3b〈/strong〉 interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 〈strong〉3b〈/strong〉. 〈em〉In vivo〈/em〉 carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 〈strong〉3b〈/strong〉 showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5 h of carrageenan injection at the 30 mg kg〈sup〉−1〈/sup〉 dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 〈strong〉3a〈/strong〉 and 〈strong〉3b〈/strong〉 present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618310320-fx1.jpg" width="421" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Siyuan Xu, Chen Zhou, Rongfeng Liu, Qihua Zhu, Yungen Xu, Fei Lan, Xiaoming Zha〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Histone lysine specific demethylase 1 (LSD1) is overexpressed in diverse hematologic disorders and recognized as a promising target for blood medicines. In this study, molecular docking-based virtual screening united with bioevaluation was utilized to identify novel skeleton of 5-arylidene barbiturate as small-molecule inhibitors of LSD1. Among the synthesized derivatives, 〈strong〉12a〈/strong〉 exhibited reversible and potent inhibition (IC〈sub〉50〈/sub〉 = 0.41 μM) and high selectivity over the MAO-A and MAO-B. Notably, 〈strong〉12a〈/strong〉 strongly induced differentiation effect on acute promyelocytic leukemia NB4 cell line and distinctly escalated the methylation level on histone 3 lysine 4 (H3K4). Our findings indicate that 5-arylidene barbiturate may represent a new skeleton of LSD1 inhibitors and 〈strong〉12a〈/strong〉 deserve as a promising agent for the further research.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618312434-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 15 November 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 21〈/p〉 〈p〉Author(s): Jesse Pulido, Maria de Cabrera, Adam J. Sobczak, Alejandro Amor-Coarasa, Anthony J. McGoron, Stanislaw F. Wnuk〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The conjugation of 4-〈em〉N〈/em〉-(3-aminopropanyl)-2′-deoxy-2′,2′-difluorocytidine with 2-(〈em〉p〈/em〉-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) ligand in 0.1 M Na〈sub〉2〈/sub〉CO〈sub〉3〈/sub〉 buffer (pH 11) at ambient temperature provided 4-〈em〉N〈/em〉-alkylgemcitabine-NOTA chelator. Incubation of latter with excess of gallium(III) chloride (GaCl〈sub〉3〈/sub〉) (0.6 N AcONa/H〈sub〉2〈/sub〉O, pH = 9.3) over 15 min gave gallium 4-〈em〉N〈/em〉-alkylgemcitabine-NOTA complex which was characterized by HRMS. Analogous [〈sup〉68〈/sup〉Ga]-complexation of 4-〈em〉N〈/em〉-alkylgemcitabine-NOTA conjugate proceeded with high labeling efficiency (94%–96%) with the radioligand almost exclusively found in the aqueous layer (∼95%). The high polarity of the gallium 4-〈em〉N〈/em〉-alkylgemctiabine-NOTA complex resulted in rapid renal clearance of the 〈sup〉68〈/sup〉Ga-labelled radioligand in BALB/c mice.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618314755-ga1.jpg" width="406" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Christina Gates, Donald S. Backos, Philip Reigan, Hye Jin Kang, Chris Koerner, Joseph Mirzaei, N.R. Natale〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR〈sub〉1a〈/sub〉, mGLuR〈sub〉5〈/sub〉 or mGluR〈sub〉8〈/sub〉. Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR〈sub〉5〈/sub〉 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR〈sub〉2〈/sub〉 and mGluR〈sub〉4〈/sub〉 are distinct: the compounds which select for mGluR〈sub〉2〈/sub〉 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA〈sub〉A,〈/sub〉 nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn’s mGluR〈sub〉1〈/sub〉 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618304462-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 September 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 17〈/p〉 〈p〉Author(s): Alberto Martínez, Mai Zahran, Miguel Gomez, Coreen Cooper, Johnny Guevara, Erik Ekengard, Ebbe Nordlander, Ralph Alcendor, Sarah Hambleton〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer’s disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β-secretase, known as BACE 1, plays a fundamental role in the production of Aβ fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs. In this work, a series of four multi-target compounds (〈strong〉1〈/strong〉–〈strong〉4〈/strong〉), inspired by previously described ionophoric polyphenols, have been synthesized and studied. These compounds have been designed to target important aspects of AD, including BACE 1 enzymatic activity, Aβ aggregation, toxic concentrations of Cu〈sup〉2+〈/sup〉 metal ions and/or ROS production. Two other compounds (〈strong〉5〈/strong〉 and 〈strong〉6〈/strong〉), previously reported by some of us as antimalarial agents, have also been studied because of their potential as multi-target species against AD. Interestingly, compounds 〈strong〉3〈/strong〉 and 〈strong〉5〈/strong〉 showed moderate to good ability to inhibit BACE 1 enzymatic activity in a FRET assay, with IC〈sub〉50〈/sub〉′s in the low micromolar range (4.4 ± 0.3 and 1.7 ± 0.3 μM, respectively), comparable to other multi-target species, and showing that the observed activity was in part due to a competitive binding of the compounds at the active site of the enzyme. Theoretical docking calculations overall agreed with FRET assay results, displaying the strongest binding affinities for 〈strong〉3〈/strong〉 and 〈strong〉5〈/strong〉 at the active site of the enzyme. In addition, all compounds selectively interacted with Cu〈sup〉2+〈/sup〉 metal ions forming 2:1 complexes, inhibited the production of Aβ-Cu〈sup〉2+〈/sup〉 catalyzed hydroxyl radicals up to a ∼100% extent, and scavenged AAPH-induced peroxyl radical species comparably to resveratrol, a compound used as reference in this work. Our results also show good anti-amyloidogenic ability: compounds 〈strong〉1〈/strong〉–〈strong〉6〈/strong〉 inhibited both the Cu〈sup〉2+〈/sup〉-induced and self-induced Aβ(1–40) fibril aggregation to an extent that ranged from 31% to 77%, while they disaggregated pre-formed Aβ(1–40) mature fibrils up to a 37% and a 69% extent in absence and presence of Cu〈sup〉2+〈/sup〉, respectively. Cytotoxicity was additionally studied in 〈em〉Tetrahymena thermophila〈/em〉 and HEK293 cells, and compared to that of resveratrol, showing that compounds 〈strong〉1〈/strong〉–〈strong〉6〈/strong〉 display lower toxicity than that of resveratrol, a well-known non-toxic polyphenol.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618313853-ga1.jpg" width="393" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 October 2018〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry, Volume 26, Issue 19〈/p〉 〈p〉Author(s): Juliet M. Alderson, Joshua R. Corbin, Jennifer M. Schomaker〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Transition metal-catalyzed nitrene transfer is a powerful method for incorporating new C〈img src="https://sdfestaticassets-eu-west-1.sciencedirectassets.com/shared-assets/16/entities/sbnd"〉N bonds into relatively unfunctionalized scaffolds. In this communication, we report the first examples of site- and chemoselective C〈img src="https://sdfestaticassets-eu-west-1.sciencedirectassets.com/shared-assets/16/entities/sbnd"〉H bond amination reactions in aqueous media. The unexpected ability to employ water as the solvent in these reactions is advantageous in that it eliminates toxic solvent use and enables reactions to be run at increased concentrations with lower oxidant loadings. Using water as the reaction medium has potential to expand the scope of nitrene transfer to encompass a variety of biomolecules and highly polar substrates, as well as enable pH control over the site-selectivity of C〈img src="https://sdfestaticassets-eu-west-1.sciencedirectassets.com/shared-assets/16/entities/sbnd"〉H bond amination.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089617324185-fx1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 30 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Qing Zhao, Guilhem Henrion, Fabien Gagosz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Gold catalysis is a convenient tool to oxidatively functionalize alkyne into a range of valuable compounds. In this article, we report a new access to isochroman-4-one and 2〈em〉H〈/em〉-pyran-3(6〈em〉H〈/em〉)-one derivatives that involves a gold-catalyzed oxidative cycloalkoxylation of an alkyne in the presence of a pyridine 〈em〉N〈/em〉-oxide. The reaction proceeds under mild conditions, is relatively efficient and exhibits a high functional group compatibility.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619301841-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 30 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Dmitrii V. Kalinin, Oriana Agoglitta, Hélène Van de Vyver, Jelena Melesina, Stefan Wagner, Burkhard Riemann, Michael Schäfers, Wolfgang Sippl, Bettina Löffler, Ralph Holl〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The Zn〈sup〉2〈/sup〉〈sup〉+〈/sup〉-dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of novel 〈span〉d〈/span〉- and 〈span〉l〈/span〉-proline-derived 3,4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3,4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, the 〈span〉l〈/span〉-proline-based tertiary amine 〈strong〉41g〈/strong〉 ((〈em〉S〈/em〉)-〈em〉N〈/em〉-hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (K〈sub〉i〈/sub〉 = 1.4 μM) over several human MMPs.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089619302354-ga1.jpg" width="290" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 29 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Min Liu, Yaqian Liu, Fan Wu, Yuhao Du, Xiang Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The DNA G-quadruplex is an important higher-order structure formed from guanine-rich DNA sequences. There are many molecules which can stabilize this structure. However, the selectivity of these ligands to different G-quadruplexes was not satisfactory. Herein, we designed and synthesized a chemically modified G-quadruplex probe, Razo-DNA, for the unique stabilization of the G-quadruplex. Razo-DNA consists of two fragments: The first is an organic molecular moiety which can stabilize G-quadruplex structures, and the second is a DNA molecule that is complementary with a sequence adjacent to the guanine-rich sequence of targeted DNA. Further studies showed that Razo-DNA could precisely stabilize the targeted DNA G-quadruplex structures in vitro.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0968089618313294-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 27 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Esben B. Svenningsen, Thomas B. Poulsen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In this paper we will outline the efforts we have made recently to establish the profiling platform known as cell painting in our laboratory. This platform, which is based on fluorescence microscopy, allows rapid and cheap access to bioactivity fingerprints for small molecules and thereby can contribute with important information in many experimental situations that is faced in laboratories involved in molecular probe design, mode-of-action studies or that perform focused phenotypic screens. We have tried to achieve the following two objectives: (1) provide a detailed description of the hurdles that we had to overcome during establishment and describe our final protocol; (2) provide a more pedagogical description of the different methods used to analyse and represent data from this experiment. Finally, we provide an example of how the method can be used to clarify mechanistic dichotomies.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961930416X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 27 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉 〈p〉Author(s): Zhao Zhang, Huajun Yu, Shang Wu, Hui Huang, Liping Si, Haiyang Liu, Lei Shi, Haitao Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Water-soluble porphyrins are considered promising drug candidates for photodynamic therapy (PDT). This study investigated the PDT activity of a new water-soluble, anionic porphyrin (〈strong〉1-Zn〈/strong〉), which possesses four negative charges. The photodynamic anticancer activity of 〈strong〉1-Zn〈/strong〉 was investigated by the MTT assay, with mTHPC as a positive control. The cellular distribution was determined by fluorescence microscopy. Holographic and phase contrast images were recorded after 〈strong〉1-Zn〈/strong〉 treatment with a HoloMonitor™ M3 instrument. The inhibition of A549 cell growth achieved by inducing apoptosis was investigated by flow cytometry and fluorescence microscopy. DNA damage was investigated by the comet assay. The expression of apoptosis-related proteins was also measured by western blot assays. 〈strong〉1-Zn〈/strong〉 had better phototoxicity against A549 cells than HeLa and HepG2 cancer cells. Interestingly, 〈strong〉1-Zn〈/strong〉 was clearly located almost entirely in the cell cytoplasmic region/organelles. The late apoptotic population was less than 1.0% at baseline in the untreated and only light-treated cells and increased to 40.5% after 〈strong〉1-Zn〈/strong〉 treatment and irradiation (P〈0.05). 〈strong〉1-Zn〈/strong〉 triggered significant ROS generation after irradiation, causing ΔΨm disruption (P〈0.01) and DNA damage. 〈strong〉1-Zn〈/strong〉 induced A549 cell apoptosis via the mitochondrial apoptosis pathway. In addition, 〈strong〉1-Zn〈/strong〉 bound in the groove of DNA via an outside binding mode by pi-pi stacking and hydrogen bonding. 〈strong〉1-Zn〈/strong〉 exhibits good photonuclease activity and might serve as a potential photosensitizer (PS) for lung cancer cells.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961930327X-ga1.jpg" width="261" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉