ALBERT

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Gyeong Han Jeong, Jae-Hyeon Cho, Tae Hoon Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Convenient structure modification of (+)-catechin (〈strong〉1〈/strong〉) induced by nonthermal dielectric barrier discharge (DBD) plasma treatment afforded three novel methylene-linked flavan-3-ol oligomers, methylenetetracatechin (〈strong〉2〈/strong〉), methylenetricatechin (〈strong〉3〈/strong〉), and methylenedicatechin (〈strong〉4〈/strong〉), together with two known catechin dimers, 〈em〉bis〈/em〉 8,8′-catechinylmethane (〈strong〉5〈/strong〉) and 〈em〉bis〈/em〉 6,8′-catechinylmethane (〈strong〉6〈/strong〉). The structures of the three new catechin oligomers 〈strong〉2〈/strong〉–〈strong〉4〈/strong〉 with methylene bridges were elucidated by detailed 1D- and 2D-NMR analysis, and the absolute configurations were established by the observation of circular dichroism (CD). The novel products 〈strong〉2〈/strong〉 and 〈strong〉3〈/strong〉 showed significantly enhanced anti-adipogenic capacities against both pancreatic lipase and differentiation of 3T3-L1 preadipocytes compared to the parent (+)-catechin.〈/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-S0960894X19304536-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 5 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Yasushi Ogasawara, Yo Nakagawa, Chitose Maruyama, Yoshimitsu Hamano, Tohru Dairi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mitomycins, produced by several 〈em〉Streptomyces〈/em〉 strains, are potent anticancer antibiotics that comprise an aziridine ring fused to a tricyclic mitosane core. Mitomycins have remarkable ability to crosslink DNA with high efficiency. Despite long clinical history of mitomycin C, the biosynthesis of mitomycins, especially mitosane core formation, remains unknown. Here, we report 〈em〉in vitro〈/em〉 characterization of three proteins, MmcB (acyl carrier protein), MitE (acyl AMP ligase), and MitB (glycosyltransferase) involved in mitosane core formation. We show that 3-amino-5-hydroxybenzoic acid (AHBA) is first loaded onto MmcB by MitE at the expense of ATP. MitB then catalyzes glycosylation of AHBA-MmcB with uridine diphosphate-〈em〉N〈/em〉-acetylglucosamine (UDP-GlcNAc) to generate a key intermediate, GlcNAc-AHBA-MmcB, which contains all carbon and nitrogen atoms of the mitosane core. These results provide important insight into mitomycin biosynthesis.〈/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-S0960894X19304548-ga1.jpg" width="490" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 4 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Hiroyuki Miyachi, Tomohiro Yuzuriha, Ryotaro Tabata, Syohei Fukuda, Kazuto Nunomura, Bangzhong Lin, Tadayuki Kobayashi, Kenji Ishimoto, Takefumi Doi, Keisuke Tachibana〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We previously reported that 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine-4-carboxylic acid derivative 〈strong〉6〈/strong〉 is an agonist of human peroxisome proliferator-activated receptor alpha (hPPARα). Here, we prepared a series of 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine-4-carboxylic acid derivatives in order to examine the structure-activity relationships (SAR). SAR studies clearly indicated that the steric bulkiness of the substituent on 1〈em〉H〈/em〉-pyrazolo-[3,4-〈em〉b〈/em〉]pyridine ring, the position of the distal hydrophobic tail part, and the distance between the distal hydrophobic tail part and the acidic head part are critical for hPPARα agonistic activity. These SAR results are somewhat different from those reported for fibrate-class hPPARα agonists. A representative compound (〈strong〉10f〈/strong〉) was as effective as fenofibrate in reducing the elevated plasma triglyceride levels in a high-fructose-fed rat 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-S0960894X19304445-ga1.jpg" width="408" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Dawanna S. White, Cindy J. Choy, Timothy W. Moural, Stacy E. Martin, Jing Wang, Samantha Gargaro, ChulHee Kang, Clifford E. Berkman〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of 〈em〉Mycobacterium tuberculosis〈/em〉 (〈em〉Mtb〈/em〉), one of the causative agents for Tuberculosis in humans. 〈em〉Mtb〈/em〉 has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (〈strong〉1〈/strong〉–〈strong〉10〈/strong〉). Substituent effects ranged from σ〈sub〉p〈/sub〉 = −0.27 to 0.78 for electronic and π = −0.41 to 1.98 for hydrophobic parameters. Compounds 〈strong〉1〈/strong〉, 〈strong〉4〈/strong〉 and 〈strong〉5〈/strong〉 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (k〈sub〉obs〈/sub〉 = 0.212, 0.324, and 0.450 mn〈sup〉−1〈/sup〉 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 〈strong〉4〈/strong〉 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme.〈/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-S0960894X19304470-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 1 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Shu-Yi Hao, Shi-Liang Feng, Xing-Rong Wang, Zhichao Wang, Shi-Wu Chen, Ling Hui〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of conjugates of podophyllotoxin and coumarin were prepared using the click reaction, and their cytotoxicities against A549, HepG2, HeLa, and LoVo cells were evaluated. Among them, compound 〈strong〉14e〈/strong〉 exhibited the strongest cytotoxicities against these cancer cells with IC〈sub〉50〈/sub〉 values of 4.9–17.5 μM. Furthermore, 〈strong〉14e〈/strong〉 disrupted microtubules and induced cell cycle arrest at G1 phase by regulating P21 and Cyclin D1 in LoVo cells. In addition, 〈strong〉14e〈/strong〉 bond CT DNA and selectively inhibited Topo IIβ over Topo IIα. Molecular docking model showed that 〈strong〉14e〈/strong〉 appeared to form stable hydrogen bonds with several DNA bases and residue Gln778. Taken together, these conjugates have the potential to be developed as anti-tumor drugs.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉The conjugates of podophyllotoxin and coumarin disrupt the microtubules, induce cell cycle arrest in G1 phase, bind to CT DNA, and inhibit Topo-Ⅱβ in LoVo cells.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19304457-ga1.jpg" width="429" 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 Letters〈/p〉 〈p〉Author(s): Phillip S. Grant, Nils Kahlcke, Karan Govindpani, Morag Hunter, Christa MacDonald, Margaret A. Brimble, Michelle Glass, Daniel P. Furkert〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The cannabinoid-1 receptor (CB1R) inverse agonist SR141716A has proven useful for study of the endocannabinoid system, including development of divalent CB1R ligands possessing a second functional motif attached via a linker unit. These have predominantly employed the C3 position of the central pyrazole ring for linker attachment. Despite this precedent, a novel series of C3-linked CB1R-D2R divalent ligands exhibited extremely high affinity at the D2R, but only poor affinity for the CB1R. A systematic linker attachment point survey of the SR141716A pharmacophore was therefore undertaken, establishing the C5 position as the optimal site for linker conjugation. This linker attachment survey enabled the identification of a novel divalent ligand as a lead compound to inform ongoing development of high-affinity CB1R molecular 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-S0960894X1930589X-ga1.jpg" width="500" 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 Letters〈/p〉 〈p〉Author(s): István Ledneczki, Zsolt Némethy, Pál Tapolcsányi, János Éles, István Greiner, Eszter Gábor, Balázs Varga, Ottilia Balázs, Viktor Román, György Lévay, Sándor Mahó〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉To further proceed with our previous work, novel steroid-based histamine H〈sub〉3〈/sub〉 receptor antagonists were identified and characterized. Using an ’amine-to-amide’ modification strategy at position 17, 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 〈strong〉10〈/strong〉 was not only highly active at human and rat H〈sub〉3〈/sub〉 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant 〈em〉in vivo〈/em〉 potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 〈strong〉10〈/strong〉 was appointed to be a preclinical candidate.〈/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-S0960894X19305888-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 29 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Lidia A. Baltina, Yan-Ting Tasi, Su-Hua Huang, Hsueh-Chou Lai, Lia A. Baltina, Svetlana F. Petrova, Marat S. Yunusov, Cheng-Wen Lin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Dengue virus (DENV) is one of the most geographically distributed pathogenic flaviviruses transmitted by mosquitoes 〈em〉Aedes sps.〈/em〉 In this study, the structure-antiviral activity relationships of Glycyrrhizic acid (GL) derivatives was evaluated by the inhibitory assays on the cytopathic effect (CPE) and viral infectivity of DENV type 2 (DENV2) in 〈em〉Vero〈/em〉 E6 cells. GL (96% purity) had a low cytotoxicity to Vero E6 cells, inhibited DENV2-induced CPE, and reduced the DENV-2 infectivity with the IC50 of 8.1 μM. Conjugation of GL with amino acids or their methyl esters and the introduction of aromatic acylhydrazide residues into the carbohydrate part strongly influenced on the antiviral activity. Among compounds tested GL conjugates with isoleucine 〈strong〉13〈/strong〉 and 11-aminoundecanoic acid 〈strong〉17〈/strong〉 were found as potent anti-DENV2 inhibitors (IC50 1.2-1.3 μM). Therefore, modification of GL is a perspective way in the search of new antivirals against DENV2 infection.〈/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-S0960894X19305906-ga1.jpg" width="345" 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 Letters〈/p〉 〈p〉Author(s): Rong-Hong Zhang, Shan Wang, Hong Zhang, Guo-Bo Xu, Yong-Long Zhao, Rui Li, Rong-Hua Luo, Yong-Jun Li, Yong-Lin Wang, Guoyi Yan, Shang-Gao Liao, Meng Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Viral infectivity factor (Vif) is one of the accessory protein of human immunodeficiency virus type I (HIV-1) that inhibits host defense factor, APOBEC3G (A3G), mediated viral cDNA hypermutations. Previous work developed a novel Vif inhibitor 2-amino-〈em〉N〈/em〉-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide (〈strong〉1〈/strong〉) with strong antiviral activity. Through optimizations on the two side branches, a series of compound 〈strong〉1〈/strong〉 derivatives (〈strong〉2〈/strong〉–〈strong〉18〈/strong〉) were designed, synthesized and tested 〈em〉in vitro〈/em〉 for their antiviral activities. The biological results showed that compound 〈strong〉5〈/strong〉 and 〈strong〉16〈/strong〉 inhibited the virus replication efficiently with EC〈sub〉50〈/sub〉 values of 9.81 and 4.62 μM. Meanwhile, low cytotoxicities on H9 cells were observed for the generated compounds by the MTT assay. The structure–activity relationship of compound 〈strong〉1〈/strong〉 was preliminarily clarified, which gave rise to the development of more potent Vif 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-S0960894X19305839-ga1.jpg" width="268" 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 Letters〈/p〉 〈p〉Author(s): Ronik Khachatoorian, Ewa D. Micewicz, Alina Micewicz, Samuel W. French, Piotr Ruchala〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Zika virus (ZIKV) has become a public health concern worldwide due to its association with congenital abnormalities and neurological diseases. To date, no effective vaccines or antiviral drugs have been approved for the treatment of ZIKV infection, and new inexpensive therapeutic options are urgently needed. In this study, we have used an 〈em〉in vitro〈/em〉 plaque assay to assess an antiviral activity of the second generation of anti-ZIKV compounds, based on 1,3-disubstituted (thio)urea scaffold. Several compounds in the library were found to possess excellent activity against Zika virus with IC〈sub〉50〈/sub〉 values 〈200 pM. The most active analog, A5 exhibited an exceptional IC〈sub〉50〈/sub〉=85.1±1.7 pM. Further analysis delineated structural requirements necessary for potent antiviral effects of this class of compounds. Collectively, our findings suggest that 1,3-disubstituted (thio)urea derivatives are excellent preclinical candidates for the development of anti-ZIKV therapeutics.〈/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-S0960894X19305682-ga1.jpg" width="500" 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 Letters〈/p〉 〈p〉Author(s): Nazmul H. Bhuiyan, Michelle L. Varney, Deep S. Bhattacharya, William M. Payne, Aaron M. Mohs, Sarah A. Holstein, David F. Wiemer〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the 〈em〉in vivo〈/em〉 biodistribution of HA-conjugated GGDPS 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-S0960894X1930575X-ga1.jpg" width="500" 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 Letters〈/p〉 〈p〉Author(s): Michael M. Wormald, Glen Ernst, Huijun Wei, James C. Barrow〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Inositol hexakisphosphate kinases (IP6Ks) have been increasingly studied as therapeutically interesting enzymes. IP6K isoform specific knock-outs have been used to successfully explore inositol pyrophosphate physiology and related pathologies. A pan-IP6K inhibitor, 〈em〉N〈/em〉2-(m-trifluorobenzyl)-〈em〉N〈/em〉6-(p-nitrobenzyl) purine (TNP), has been used to confirm phenotypes observed in genetic knock-out experiments; however, it suffers by having modest potency and poor solubility making it difficult to handle for 〈em〉in vitro〈/em〉 applications in the absence of DMSO. Moreover, TNP’s pan-IP6K inhibitory profile does not inform which IP6K isoform is responsible for which phenotypes. In this report we describe a series of purine-based isoform specific IP6K1 inhibitors. The lead compound was identified after multiple rounds of SAR and has been found to selectively inhibit IP6K1 over IP6K2 or IP6K3 using biochemical and biophysical approaches. It also boasts increased solubility and IP6K1 potency over TNP. These new compounds are useful tools for additional assay development and exploration of IP6K1 specific biology.〈/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-S0960894X19305700-ga1.jpg" width="500" 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 Letters〈/p〉 〈p〉Author(s): Lee McDermott, David Koes, Shabber Mohammed, Prema Iyer, Melissa Boby, Venkatakrishnan Balasubramanian, Mackenzie Geedy, William Katt, Richard Cerione〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Allosteric inhibitors of glutaminase (GAC), such as BPTES, CB-839 and UPGL00019, have great promise as inhibitors of cancer cell growth, but potent inhibitors with drug-like qualities have been difficult to achieve. Here, a small library of GAC inhibitors based on the UPGL00019 core is described. This set of derivatives was designed to assess if one or both of the phenylacetyl groups flanking the UPGL00019 core can be replaced by smaller simple aliphatic acyl groups without loss in potency. We found that one of the phenylacetyl moieties can be replaced by a set of small aliphatic moieties without loss in potency. We also found that enzymatic potency co-varies with the VDW volume or the maximum projection area of the groups used as replacements of the phenylacetyl moiety and used literature X-ray data to provide an explanation for this finding.〈/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-S0960894X19305748-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 Letters〈/p〉 〈p〉Author(s): Tomoaki Anabuki, Yusuke Ito, Keisuke Ohashi, Taichi E. Takasuka, Hideyuki Matsuura, Kosaku Takahashi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Target protein identification of bioactive small molecules is one of the most important research in forward chemical genetics. The affinity chromatography technique to use a resin bound with a small molecule is often used for identification of a target protein of a bioactive small molecule. Here we report a new method to isolate a protein targeted with a bioactive small molecule using a biotin linker with alkyne and amino groups, protein cross-linker containing disulfide bond, and a bioactive small molecule with an azido group (azido probe). After an azido probe is associated with a target protein, the complex of a target protein and azido probe is covalently bound through the biotin linker by azide-alkyne Huisgen cycloaddition and protein cross-linker containing disulfide bond. This ternary complex is immobilized on an affinity matrix with streptavidin, and then the target protein is selectively eluted with a buffer containing a reducing agent for cleavage of disulfide bonds. This method uses a probe having an azido group, which a small functional group, and has the possibility to be a solution strategy to overcome the hindrance of a functional group introduced into the probe that reduces association a target protein. The effectiveness of the method in this study was shown using linker 〈strong〉1〈/strong〉, 3’-azidoabscisic acid 〈strong〉3〈/strong〉, and protein cross-linker containing a disulfide bond (DTSSP 〈strong〉5〈/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-S0960894X19305761-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Lihua Shao, Yue Bai, Qiutang Wang, Zizhang Chen, Yundong Xie, Xiaoli Bian〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Six novel target compounds 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT) based fibrates were synthesized and evaluated. All the synthesized compounds were preliminarily screened by using the Triton WR-1339-induecd hyperlipidemia model, in which T1 exhibited more potent hypolipidemic property than positive drug fenofibrate (FF). T1 also significantly decreased serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in methionine solution (Mets) induced hyperlipidemic mice. Moreover, hepatic transaminases (AST and ALT) were obviously ameliorated after treatment with T1 and the histological observation indicated that T1 ameliorated the injury in liver tissue and inhibited the hepatic lipid accumulation. In the livers of T1-administrated rat, the levels of PPARα related to lipids metabolism were up-regulated. Additional effects such as antioxidant, anti-inflammatory and H〈sub〉2〈/sub〉S releasing action confirmed and reinforced the activity of T1 as a potential multifunctional hypolipidemic and hepatoprotective agent.〈/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-S0960894X1930681X-ga1.jpg" width="369" 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 Letters〈/p〉 〈p〉Author(s): Takeshi Fuchigami, Kohnosuke Itagaki, Natsumi Ishikawa, Sakura Yoshida, Morio Nakayama〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Legumain or asparaginyl endopeptidase is an enzyme overexpressed in some cancers and involved in cancer migration, invasion, and metastasis. We have developed radioiodine- ([〈sup〉125〈/sup〉I]I-LCP) or fluorescein-labeled peptides (FL-LCP) with a cell-permeable 〈span〉d〈/span〉-Arg nonamer fused to an anionic 〈span〉d〈/span〉-Glu nonamer via a legumain-cleavable linker, to function as peptide probes that measure and monitor legumain activity. Non-cleavable probes of FL-NCP and [〈sup〉125〈/sup〉I]I-NCP were similarly prepared and evaluated as negative control probes by altering their non-cleavable sequence. Model peptides with the legumain-cleavable or non-cleavable sequence (LCP and NCP, respectively) reacted with recombinant human legumain, and only LCP was digested by this enzyme. [〈sup〉125〈/sup〉I]I-LCP uptake in legumain-positive HCT116 cells was significantly higher than that of [〈sup〉125〈/sup〉I]I-NCP (11.2 ± 0.44% vs 1.75 ± 0.06% dose/mg). The accumulation of FL-LCP in the HCT116 cells was rather low (4.75 ± 0.29% dose/mg protein), but not significantly different from the levels of FL-NCP. It is possible that low concentrations of [〈sup〉125〈/sup〉I]I-LCP (40 pM) can be effectively internalized after legumain cleavage. On the other hand, the cellular uptake of much higher concentrations of the FL-LCP derivative (1 mM) may be restricted by high concentrations of polyanions. The 〈em〉in vivo〈/em〉 biodistribution studies in tumor-bearing mice demonstrated that the tumor uptake of [〈sup〉125〈/sup〉I]I-LCP was 1.34% injected dose per gram (% ID/g) at 30 min. The tumor/blood and tumor/muscle ratios at 30 min were 0.63 and 1.77, respectively, indicating that the [〈sup〉125〈/sup〉I]I-LCP accumulation in tumors was inadequate for 〈em〉in vivo〈/em〉 imaging. Although further structural modifications are necessary to improve pharmacokinetic properties, [〈sup〉125〈/sup〉I]I-LCP has been demonstrated to be an effective scaffold for the development of nuclear medicine imaging probes to monitor legumain activity in living subjects.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉We report here radioiodine-labeled peptide ([〈sup〉125〈/sup〉I]I-LCP) with a cell-permeable 〈span〉d〈/span〉-Arg nonamer fused to an anionic 〈span〉d〈/span〉-Glu nonamer via a legumain-cleavable linker to monitor legumain activity in cancers.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19305712-ga1.jpg" width="362" 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 Letters〈/p〉 〈p〉Author(s): Qiaoling Xu, Baozhu Dai, Zhiwei Li, Le Xu, Di Yang, Ping Gong, Yunlei Hou, Yajing Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-〈em〉N,N〈/em〉′-dimethylacetamide moiety as the linker. The cell proliferation assay 〈em〉in vitro〈/em〉 against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 〈strong〉12c〈/strong〉 and 〈strong〉12g〈/strong〉 were potent FLT3 inhibitors with IC〈sub〉50〈/sub〉 values of 312 nM and 384 nM, respectively. Following that, molecular docking analysis was also performed to determine possible binding mode between FLT3 and the target compound.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N′-dimethylacetamide moiety as linker were designed, synthesized and evaluated for their biological activity.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19305724-ga1.jpg" width="312" 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 Letters〈/p〉 〈p〉Author(s): Harpreet Singh, Manpreet Kaur, Harpreet Kaur, Indu Sharma, Anmol Bhandari, Gurcharan Kaur, Palwinder Singh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Targeting dihydrofolate reductase, here, we report the tumor growth inhibitory activity of substituted acridones. The screening of the molecules over 60 cell line panel of human cancer cells identified (〈em〉S〈/em〉)-oxiran-2-ylmethyl 9-oxo-9,10-dihydroacridine-4-carboxylate (〈strong〉19〈/strong〉) with average GI〈sub〉50〈/sub〉 0.3 μM. The specificity of the compound to CCRF-CEM, MOLT-4 and SR cell lines of leukemia and SW-620, SF268, LOXIMVI, ACHN and MCF7 cancerous cells exhibiting GI〈sub〉50〈/sub〉 in the nM range was observed. C6 Glioma cells treated with compound 〈strong〉19〈/strong〉 showed differentiated cell morphology and cell cycle arrest in G2/M phase. The interactions of the compound with dihydrofolate reductase were ascertained with the help of enzyme immunoassays, molecular docking and molecular dynamic studies.〈/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-S0960894X19305736-ga1.jpg" width="472" 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 Letters, Volume 29, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 14 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Shuangmei Zhao, Yongqi Zhen, Leilei Fu, Feng Gao, Xianli Zhou, Shuai Huang, Lan Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Sodium taurocholate cotransport polypeptide (NTCP) plays an important role in the development of hepatitis and acts as a switch to allow hepatitis virus to enter hepatic cells. As the entry receptor protein of hepatitis virus, NTCP is also an effective target for the treatment of hepatocellular carcinoma. Herein, twenty-five benzamide analogues were synthesized based on the virtual screening design and their anti-proliferative activities against HepG2 cells were evaluated 〈em〉in vitro〈/em〉. Compound 〈strong〉35〈/strong〉 was found to be promising, with an IC〈sub〉50〈/sub〉 value of 2.8 μM. The apoptosis induced by 〈strong〉35〈/strong〉 was characterized by the regulation of markers, including an increase in Bax, cleaved-caspase 3, and cleaved-PARP proteins, and a decrease in Bcl-2 protein. Molecular docking and molecular dynamics (MD) simulation confirmed that compound 〈strong〉35〈/strong〉 can bind tightly to NTCP. Western blot analysis also showed that NTCP was inhibited. Altogether, these results indicate that compound 〈strong〉35〈/strong〉 acts as a novel NTCP inhibitor to induce apoptosis in HepG2 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-S0960894X19305530-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Cong Zhang, Yan Wu, Jie Li, Gui-Xiang Yang, Lin Su, Yan Huang, Rui Wang, Lei Ma〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Studies indicated that smilagenin, isolated from 〈em〉Anemarrhena asphodeloides〈/em〉 Bunge, could improve cognitive impairment and exhibit neuroprotective activity. On the basis of the structure of smilagenin, a series of derivatives were synthesized and evaluated for their neuroprotective effects of H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉-induced, oxygen glucose deprivation-induced neurotoxicity in SH-SY5Y cells and LPS-induced NO production in RAW264.7 cells. Structure activity relationship of derivatives revealed that benzyl-substituted piperazine formate derivatives showed the potent neuroprotective activity such as 〈strong〉A12〈/strong〉. These findings may provide new insights for the development of neuroprotective agents against Alzheimer’s disease.〈/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-S0960894X19305529-ga1.jpg" width="357" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 12 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Aleksandra A. Moiseeva, Oleg I. Artyushin, Lada V. Anikina, Valery K. Brel〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The design of hybrid (chimeric) molecules containing two different pharmacophores connected via a spacer (linker) is a promising approach to the functionalization of natural compounds and potentially of drug molecules. These are important examples for the use of this approach with anthracycline antibiotics. The use of this methodology may help to eliminate some of the drawbacks of anthracycline drugs, e.g., high cardiotoxicity and MDR development.〈/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-S0960894X19305499-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 Letters〈/p〉 〈p〉Author(s): Alistair O'Brien, Steve Andrews, Asma H. Baig, Andrea Bortolato, Alastair J.H. Brown, Giles A. Brown, Sue H. Brown, John A. Christopher, Miles Congreve, Robert M. Cooke, Chris De Graaf, James C. Errey, Charlotte Fieldhouse, Ali Jazayeri, Fiona H. Marshall, Jonathan S. Mason, Juan Carlos Mobarec, Krzysztof Okrasa, Kelly N. Steele, Stacey M. Southall〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C347〈sup〉6.36b〈/sup〉 of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described.〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19305426-ga1.jpg" width="298" 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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Sateesh Kumar Arepalli, Chaerim Lee, Jae-Kyung Jung, Youngsoo Kim, Kiho Lee, Heesoon Lee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We have designed and synthesized twenty-six 〈em〉N〈/em〉-arylindazole-3-carboxamide (〈strong〉3a-p〈/strong〉) and 〈em〉N〈/em〉-benzoylindazole (〈strong〉6a-j〈/strong〉) derivatives to discover with excellent inhibition activities of α-MSH-stimulated melanogenesis. In the bio evaluation studies of these compounds, we discovered eighteen compounds, out of twenty-six exhibited more potent inhibition than the positive control arbutin. From the SAR studies, we identified 〈strong〉3k〈/strong〉 and 〈strong〉6g〈/strong〉 as lead compounds which displayed almost 5 and 9 times more potent inhibition of α-MSH-stimulated melanogenesis respectively than the reference arbutin. It is also evident the presence of electron withdrawing group at para position (R〈sup〉3〈/sup〉) for the compounds (〈strong〉3a-p〈/strong〉) and presence of +M group at ortho position (R〈sup〉5〈/sup〉) for the compounds (〈strong〉6a-j〈/strong〉) were crucial for their excellent inhibition activities of α-MSH-stimulated melanogenesis.〈/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-S0960894X19305268-ga1.jpg" width="369" 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 Letters〈/p〉 〈p〉Author(s): Tapasi Manna, Kunal Pal, Kuladip Jana, Anup Kumar Misra〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of glycosylated 1,4-substituted triazolyl chalcone derivatives (〈strong〉8a-f〈/strong〉 and 〈strong〉14a-r〈/strong〉) were synthesized in high yield using 1,3-cycloaddition (Click chemistry) of 〈span〉d〈/span〉-glucosyl azides with a variety of propargylated chalcone derivatives followed by de-〈em〉O〈/em〉-acetylation. The synthesized compounds were evaluated for their cytotoxic potential against the human breast carcinoma cell lines and non-cancerous cells. The MTT assay identified three promising cytotoxic compounds (〈strong〉14c〈/strong〉, 〈strong〉14i〈/strong〉 and 〈strong〉14l〈/strong〉) and further biochemical and microscopic studies were carried out with the best compound 〈strong〉14i〈/strong〉 among the active 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-S0960894X19305475-ga1.jpg" width="399" 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 Letters〈/p〉 〈p〉Author(s): Gaofeng Zhu, Keren Wang, Jian Shi, Pengfei Zhang, Dan Yang, Xiaotian Fan, Ziyi Zhang, Wenmin Liu, Zhipei Sang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound 〈strong〉TM-14〈/strong〉 showed the best 〈em〉ee〈/em〉AChE inhibitory activity with IC〈sub〉50〈/sub〉 value of 2.9 μM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that 〈strong〉TM-14〈/strong〉 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 〈strong〉TM-14〈/strong〉 was a selective metal chelator and could form 1:1 〈strong〉TM-14〈/strong〉-Cu〈sup〉2+〈/sup〉 complex. The structure-active-relationship also indicated that the 〈em〉O〈/em〉-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound 〈strong〉TM-2〈/strong〉 exhibited potent hMAO-B inhibitory activity (IC〈sub〉50〈/sub〉 = 6.8 μM), which was supported by the molecular docking study. More interestingly, compounds 〈strong〉TM-14〈/strong〉 and 〈strong〉TM-2〈/strong〉 could cross the blood-brain barrier 〈em〉in vitro〈/em〉. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer’s disease.〈/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-S0960894X19305670-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 17 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Yonghui Xie, Haojie Huang, Ismail Ismail, Hongyan Sun, Long Yi, Zhen Xi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Based on thiolysis of the NBD amine, a H〈sub〉2〈/sub〉S-triggered prodrug has been designed and synthesized for localized production of ciprofloxacin under micromolar H〈sub〉2〈/sub〉S. Activation of the prodrug can be monitored through fluorescence in real-time. We envision that thiolysis of the NBD amine could be readily used for development of other H〈sub〉2〈/sub〉S-triggered prodrugs in the future.〈/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-S0960894X19305694-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 16 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Charles G. Clark, Karen A. Rossi, James R. Corte, Tianan Fang, Joanne M. Smallheer, Indawati De Lucca, David S. Nirschl, Michael J. Orwat, Donald J.P. Pinto, Zilun Hu, Yufeng Wang, Wu Yang, Yoon Jeon, William R. Ewing, Joseph E. Myers, Steven Sheriff, Zhen Lou, Jeffrey M. Bozarth, Yiming Wu, Alan Rendina〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 〈strong〉9〈/strong〉. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 〈strong〉10〈/strong〉, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 〈strong〉9〈/strong〉. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.〈/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-S0960894X19305347-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 12 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Tejshri R. Deshmukh, Aniket P. Sarkate, Deepak K. Lokwani, Shailee V. Tiwari, Rajaram Azad, Bapurao B. Shingate〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (〈strong〉7a〈/strong〉–〈strong〉j〈/strong〉) by using 1,3-dipolar cycloaddition reaction between 2-azido-〈em〉N〈/em〉-phenylacetamides (〈strong〉4a〈/strong〉–〈strong〉e〈/strong〉) and bis(prop-2-yn-1-yloxy)benzenes (〈strong〉6a〈/strong〉–〈strong〉b〈/strong〉) 〈em〉via〈/em〉 copper (I)-catalyzed click chemistry approach with good to excellent yields. All the newly synthesized compounds have been screened for their 〈em〉in vitro〈/em〉 antiproliferative activities against two human cancer cell lines. The compounds 〈strong〉7d〈/strong〉, 〈strong〉7e〈/strong〉, 〈strong〉7h〈/strong〉, 〈strong〉7i〈/strong〉 and 〈strong〉7j〈/strong〉 have revealed promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 〈strong〉7a〈/strong〉, 〈strong〉7b〈/strong〉, 〈strong〉7c〈/strong〉, 〈strong〉7i〈/strong〉 and 〈strong〉7j〈/strong〉 were observed as potent antiproliferative agents against human lung cancer cell line (A-549). The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic study, which shows that the compounds 〈strong〉7d〈/strong〉, 〈strong〉7h〈/strong〉 and 〈strong〉7j〈/strong〉 were acts as active EGFR tyrosine kinase phosphorylation inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all the newly synthesized hybrids were predicted.〈/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-S0960894X19305463-ga1.jpg" width="483" 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 Letters, Volume 29, Issue 16〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 15 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Ayse Okesli-Armlovich, Amita Gupta, Marta Jimenez, Douglas Auld, Qi Liu, Michael C. Bassik, Chaitan Khosla〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Clinically relevant inhibitors of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in mammalian de novo pyrimidine synthesis, have strong antiviral and anticancer activity 〈em〉in vitro〈/em〉. However, they are ineffective 〈em〉in vivo〈/em〉 due to efficient uridine salvage by infected or rapidly dividing cells. The pyrimidine salvage enzyme uridine-cytidine kinase 2 (UCK2), a ∼29 kDa protein that forms a tetramer in its active state, is necessary for uridine salvage. Notwithstanding the pharmacological potential of this target, no medicinally tractable inhibitors of the human enzyme have been reported to date. We therefore established and miniaturized an 〈em〉in vitro〈/em〉 assay for UCK2 activity and undertook a high-throughput screen against a ∼40,000-compound library to generate drug-like leads. The structures, activities, and modes of inhibition of the most promising hits are described. Notably, our screen yielded non-competitive UCK2 inhibitors which were able to suppress nucleoside salvage in cells both in the presence and absence of DHODH 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-S0960894X19305360-ga1.jpg" width="422" 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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Surendar Chitti, SrinivasaRao Singireddi, Pochana Santosh Kumar Reddy, Prakruti Trivedi, Yamini Bobde, Chandan Kumar, Krishnan Rangan, Balaram Ghosh, Kondapalli Venkata Gowri Chandra Sekhar〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Two series of forty five novel 2-(3,4-dimethoxyphenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl) imidazo[1,2-〈em〉a〈/em〉]pyridine analogues (〈strong〉IPA 1〈/strong〉–〈strong〉22〈/strong〉, 〈strong〉IPS 1〈/strong〉–〈strong〉22〈/strong〉 and 〈strong〉IP-NH〈/strong〉) have been designed, synthesized and structures confirmed by 〈sup〉1〈/sup〉H NMR, 〈sup〉13〈/sup〉C NMR, mass spectrometry. Furthermore, single crystal was developed for 〈strong〉IPS-13〈/strong〉. All the final derived conjugates were evaluated for their 〈em〉in vitro〈/em〉 antiproliferative activity against a panel of diverse cancer cell lines viz., A549 (lung cancer), HeLa (cervical cancer), B16F10 (melanoma) and found to show potent anticancer activity on the tested cell lines. Many of them showed the IC〈sub〉50〈/sub〉 values in the range 2.0–20.0 µM. The most active compounds (〈strong〉IPA 5,6,8,9,12,16,17,19〈/strong〉 and 〈strong〉IPS 7,8,9,22〈/strong〉) from IPA and IPS series were screened to determine their cytotoxicity on HEK-293 (human embryonic kidney) normal cell line and were found to be nontoxic to normal human cells. The molecular interactions of the derivatised conjugates were also supported by molecular docking simulations. These derivatives may serve as lead structures for development of novel potential anticancer 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-S0960894X19305396-ga1.jpg" width="294" 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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Jingxin Qiao, Guifeng Lin, Anjie Xia, Zhiyu Xiang, Pei Chen, Guo Zhang, Linli Li, Shengyong Yang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Inhibitors of the Hippo signaling pathway have been demonstrated to have a potential clinical application in cases such as tissue repair and organ regeneration. However, there is a lack of potent Hippo pathway inhibitors at present. Herein we report the discovery of a series of 1,8-disubstituted-[1,2,3]triazolo[4,5-〈em〉c〈/em〉]quinoline derivatives as a new class of Hippo pathway inhibitors by utilizing a cell line-based screening model (A549-CTGF). Structure-activity relationship (SAR) of these compounds was also discussed. The most potent compound in the A549-CTGF cell assay, 〈strong〉11g〈/strong〉, was then evaluated by real-time PCR and immunofluorescence assays. Overall, this study provides a starting point for later drug discovery targeting the Hippo signaling pathway.〈/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-S0960894X1930527X-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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Roksana Trznadel, Aleksandra Singh, Natalia Kleczewska, Joanna Liberska, Piotr Ruszkowski, Lech Celewicz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Two series of novel gemcitabine-nucleoside analogue dimers were synthesized using the ‘click’ chemistry approach. In the first series of dimers (〈strong〉21〈/strong〉–〈strong〉30〈/strong〉), the nucleoside units were connected with a stable methyltriazole 4〈em〉N〈/em〉-3′(or 5′)〈em〉C〈/em〉 linker whereas in the second series (〈strong〉31〈/strong〉–〈strong〉40〈/strong〉) with a cleavable ester-methyltriazole 4〈em〉N〈/em〉-3′(or 5′)〈em〉C〈/em〉 linker. Dimers 〈strong〉21〈/strong〉–〈strong〉40〈/strong〉 were evaluated for their cytotoxic activity in five human cancer cell lines such as cervical (HeLa), nasopharyngeal (KB), lung (A549), brain (U87), liver (HepG2) and normal dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Compound 〈strong〉29〈/strong〉 comprising two gemcitabine (dFdC) units exhibited the highest activity among dimers 〈strong〉21〈/strong〉–〈strong〉30〈/strong〉. The activity of compound 〈strong〉29〈/strong〉 was higher than that of dFdC in all the studied cancer cell lines. A similar order of activity was observed for compounds 〈strong〉25〈/strong〉, 〈strong〉28〈/strong〉, and 〈strong〉30〈/strong〉. The best activity among all the dimers synthesized was displayed by compound 〈strong〉39〈/strong〉, comprising two gemcitabine units with a cleavable linker. The activity of compound 〈strong〉39〈/strong〉 was 5 to 9 times higher than that of dFdC, depending on the cell line. In addition, marked cytotoxic activity was shown by compounds 〈strong〉31〈/strong〉, 〈strong〉36〈/strong〉, 〈strong〉38〈/strong〉, and 〈strong〉40〈/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-S0960894X19305293-ga1.jpg" width="354" 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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Peter S. Thuy-Boun, Dennis W. Wolan〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉To identify sialic acid binding proteins from complex proteomes, three photocrosslinking affinity-based probes were constructed using Neu5Ac (〈strong〉5〈/strong〉 and 〈strong〉6〈/strong〉) and Neu5Ac2en (〈strong〉7〈/strong〉) scaffolds. Kinetic inhibition assays and Western blotting revealed the Neu5Ac2en-based 〈strong〉7〈/strong〉 to be an effective probe for the labeling of a purified gut microbial sialidase (BDI_2946) and a purified human sialic acid binding protein (hCD33). Additionally, LC–MS/MS affinity-based protein profiling verified the ability of 〈strong〉7〈/strong〉 to enrich a low-abundance sialic acid binding protein (complement factor H) from human serum thus validating the utility of this probe in a complex context.〈/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-S0960894X19305256-ga1.jpg" width="313" 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 Letters, Volume 29, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 1 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 17〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 16 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Govindan Subramanian, Scott J. Bowen, Yaqi Zhu, Nicole Roush, Theresa Zachary, Christopher Javens, Tracey Williams, Ann Janssen, Andrea Gonzales〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉In silico〈/em〉 virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 〈strong〉1a〈/strong〉 and 〈strong〉2a〈/strong〉 exhibiting nanomolar affinity in the kinase domain only 〈em〉h〈/em〉TrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 〈strong〉1a〈/strong〉 and 〈strong〉2a〈/strong〉, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of 〈em〉h〈/em〉TrkA…〈strong〉1a〈/strong〉/〈strong〉2a〈/strong〉 complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and αC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length 〈em〉h〈/em〉TrkA cell-based assay and selectivity against the closely related 〈em〉h〈/em〉TrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression.〈/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-S0960894X19305542-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Rambabu Dakarapu, Ramu Errabelli, Vijaya L. Manthati, Adeniyi Michael Adebesin, Deb K. Barma, Deepan Barma, Victor Garcia, Fan Zhang, Michal Laniado Schwartzman, John R. Falck〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉19-Hydroxyeicosatetraenoic acid (19-HETE, 〈strong〉1〈/strong〉), a metabolically and chemically labile cytochrome P450 eicosanoid, has diverse biological activities including antagonism of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE, 〈strong〉2〈/strong〉). A SAR study was conducted to develop robust analogs of 〈strong〉1〈/strong〉 with improved 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 efficacy. Analogs were screened 〈em〉in vitro〈/em〉 for inhibition of 20-HETE-induced sensitization of rat renal preglomerular microvessels toward phenylephrine and demonstrated to normalize the blood pressure of male Cyp4a14(-/-) mice that display androgen-driven, 20-HETE-dependent hypertension.〈/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-S0960894X19305487-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 12 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Mohd Adil Shareef, Kanugala Sirisha, Ibrahim Bin Sayeed, Irfan Khan, Thipparapu Ganapathi, Syed Akbar, C. Ganesh Kumar, Ahmed Kamal, Bathini Nagendra Babu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of new triazole fused imidazo[2,1-〈em〉b〈/em〉]thiazole hybrids (〈strong〉9a〈/strong〉〈em〉–〈/em〉〈strong〉u〈/strong〉) were designed, synthesized and evaluated as antimicrobial agents. Compounds 〈strong〉9c〈/strong〉, 〈strong〉9d〈/strong〉, 〈strong〉9e〈/strong〉, 〈strong〉9j〈/strong〉 and 〈strong〉9l〈/strong〉 showed promising broad spectrum antimicrobial activity. Further, compound 〈strong〉9c〈/strong〉 exhibited significant anti-biofilm activity with single and mixed biofilm disruption demonstrated by Field Emission Scanning Electron Microscope (FE-SEM). Furthermore, molecular docking studies revealed that they interact with the virulence factor, 〈em〉Staphylococcus aureus〈/em〉 dehydrosqualene synthase (CrtM) (PDB ID: 2ZCS). Overall, the findings suggest compound 〈strong〉9c〈/strong〉 as potential lead for further development of novel antibacterial and anti-biofilm 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-S0960894X19305451-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 12 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Vineeta Rustagi, D. Gomika Udugamasooriya〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The metal-chelated 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-tetraamide (DOTA) scaffold has been widely used as a contrast agent for diagnostic purposes in positron emission tomography (PET) and magnetic resonance imaging (MRI), but not as a biomarker targetable ligand. While the oxygen atoms at the stem of the four arms of the DOTA scaffold are needed for metal chelation, we previously introduced various physiochemical properties to extend these arms in a chemical library fashion to enhance the imaging contrast mechanism. We developed two such on-bead libraries, with 80 and 76 DOTA derivatives, where one arm was used to attach the DOTA scaffold onto resin beads and the other three arms were chemically modified. We now hypothesized that the chemical moieties used to modify these three arms can also recognize biomarkers on a cell surface. Therefore in this current study, we used such 76 derivatives of DOTA library to screen against HeLa cervical cancer cells. We found that two of the four ‘hits’ identified displayed higher binding towards HeLa cells than the unmodified parent DOTA. Furthermore, one of those ‘hits’ displayed better binding towards cervical and prostate cancer cells than lung and breast cancer cells and normal HBEC-3KT and RWPE1 cells. This indicates that this derivative can recognize a biomarker specific for certain types of cancer cells. If the compound has intrinsic activity, this can be used as a theranostic agent for real time therapy monitoring applications in the future. We believe that our DOTA derivative-based library approach can be applied to other types of cell and protein screens on various disease types in the future.〈/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-S0960894X19305505-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 Letters〈/p〉 〈p〉Author(s): K. Lutsenko, S. Hagenow, A. Affini, D. Reiner, H. Stark〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The irreversible monoamine oxidase B (MAO B) inhibitor rasagiline has been described with multiple disease modifying effects in vitro on models of Parkinson’s disease. The combination of this established drug to recently developed histamine H〈sub〉3〈/sub〉 receptor (H〈sub〉3〈/sub〉R) antagonist elements gives new impetus to the design of multitargeting ligands. Surprisingly, the 5-substituted 3-piperidinopropyloxy rasagiline derivative 〈strong〉1〈/strong〉 was more potent on both targets than its 6-substituted isomer. It showed nanomolar affinities at the desired targets (MAO B IC〈sub〉50〈/sub〉 = 256 nM; hH〈sub〉3〈/sub〉R K〈sub〉i〈/sub〉 = 2.6 nM) with a high preference over monoamine oxidase A (MAO A) and negligible affinity at histamine H〈sub〉1〈/sub〉, H〈sub〉4〈/sub〉, dopamine D〈sub〉2〈/sub〉, D〈sub〉3〈/sub〉 receptors or acetyl-/butyrylcholinesterases.〈/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-S0960894X19305402-ga1.jpg" width="305" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 10 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Qi Chen, Alexander Smith〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The potent antiviral properties of 3-deazaneplanocin, 3-deaza-isoneplanocins (〈strong〉1〈/strong〉) and recently discovered 〈span〉l〈/span〉-like carbocyclic nucleosides (〈strong〉2〈/strong〉, 〈strong〉3〈/strong〉 and 〈strong〉4〈/strong〉) prompted us to pursue rationally conceived 〈span〉l〈/span〉-like 3-deazaneplanocin analogues. The synthesis of those analogues including 〈span〉l〈/span〉-like 3-deazaneplanocin (〈strong〉5〈/strong〉), 〈span〉l〈/span〉-like 3-bromo-3-deazaneplanocin (〈strong〉6〈/strong〉), and 〈span〉l〈/span〉-like 5′-fluoro-5′-deoxy-3-deazaneplanocin (〈strong〉7〈/strong〉), was accomplished from a common intermediate, (−)-cyclopentenone (〈strong〉8〈/strong〉). Antiviral analysis found 〈strong〉5〈/strong〉 and 〈strong〉6〈/strong〉 to display favorable activity against the Ebola virus, as expected for 3-deazaadenine carbocyclic nucleosides. Compound 〈strong〉5〈/strong〉 also showed activity against arenaviruses, including Pinchinde and Tacaribe.〈/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-S0960894X19305438-ga1.jpg" width="419" 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 Letters, Volume 29, Issue 16〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Yongxi Dong, Xiaohe Zhang, Mingji Liu, Yang Yang, Ting Guo, Yuanhu Mao, Jiquan Zhang, Xiaozhong Fu, Yonglong Zhao, Jinglei Chen, Li Dong, Chunhua Qiao〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of hybrid molecules of scutellarein and tertramethylpyrazine’s active metabolites have been synthesized. Compared to the original compound, these prepared compounds exhibited higher water solubility, more appropriate logP and better stability. Importantly, compounds 〈strong〉11b〈/strong〉, 〈strong〉11d〈/strong〉 and 〈strong〉11e〈/strong〉 showed improved neuroprotective activity against the H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉-induced cell death in PC12 cells, and better antithrombosis activity. The optimized compound 〈strong〉11b〈/strong〉 was further evaluated by cerebral ischemia/ reperfusion in the middle cerebral artery occlusion (MCAO) model, the results showed that the compound could significantly reduce the infarct area and decrease the neuronal cell damage in CA1 pyramidal neurons. Overall, we demonstrated that the twin drug strategy could be applied in the development of agents for the treatment of ischemic stroke.〈/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-S0960894X19305384-ga1.jpg" width="307" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Augustine T. Osuma, Xiangdong Xu, Zhi Wang, Jennifer A. Van Camp, Gail M. Freiberg〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Effective treatments of neuropathic pain have been a focus of many discovery programs. KCNQ (kv7) are voltage gated potassium channel openers that have the potential for the treatment of CNS disorders including neuropathic pain. Clinical studies have suggested agents such as Retigabine to be a modulator of pain-like effects such as hyperalgesia and allodynia. In this paper, we describe the discovery and evaluation of a series of novel pyrazolopyrimidines and their affinity for potassium channels KCNQ2/3. These pyrazolopyrimidines have also shown good efficacy in the capsaicin-induced acute and secondary mechanical allodynia model and excellent pharmacokinetic properties, which may be superior to Retigabine.〈/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-S0960894X19305335-ga1.jpg" width="447" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Gen Li, Mamateli Obul, Jiang-yu Zhao, Ge-yu Liu, Wei Lu, Haji Akber Aisa〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In spired by the important role of amide groups of anti-influenza drugs oseltamivir, zanamivir and peramivir in bioactivity, a series of novel amides modified rupestonic acid derivatives were designed and synthesized. The absolute configuration of critical intermediate bearing chloride with newly formed stereocenter was confirmed by X-ray crystallographic analysis. And all new compounds were evaluated for their 〈em〉in vitro〈/em〉 inhibitory activities against influenza A (H1N1 and H3N2) and influenza B viruses. The bioassay results showed that 〈strong〉5h〈/strong〉 with 4-fluorbenzylsulfonyl modified to 2 position of methyl rupestonate displayed the highest activity against influenza A (H1N1 and H3N2) viruses, even stronger than reference drugs oseltamivir and ribavirin (RVB), and might be recommended as a lead compound to further develop the new anti-influenza reagent.〈/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-S0960894X19305359-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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Feyisola P. Olatunji, Brittany N. Kesic, Cindy J. Choy, Clifford E. Berkman〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈span〉l〈/span〉-Dopa has continued to be a mainstay in the symptomatic treatment of Parkinson’s disease (PD). However, extensive peripheral metabolism, a short systemic circulation half-life and development of motor complications called dyskinesia prevents its long-term utilization as a PD therapeutic. Herein, we report a series of phosphoramidate derivatives of 〈span〉l〈/span〉-Dopa and controlled release of 〈span〉l〈/span〉-Dopa at pH 7.4 and 3. The kinetic data for the release of 〈span〉l〈/span〉-Dopa support our hypothesis that a proximal carboxylic acid can promote the pH-triggered hydrolysis of the phosphoramidate P〈img src="https://sdfestaticassets-eu-west-1.sciencedirectassets.com/shared-assets/16/entities/sbnd"〉N bond. As expected, esterification of the proximal carboxylic acid protects the scaffold from rapid release at low pH. This latter observation is particularly noteworthy as it suggests that the phosphoramidate-based 〈span〉l〈/span〉-Dopa−conjugate scaffold can be adapted for oral administration as an ester prodrug.〈/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-S0960894X19305311-ga1.jpg" width="438" 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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Xavier Fradera, Joey L. Methot, Abdelghani Achab, Matthew Christopher, Michael D. Altman, Hua Zhou, Meredeth A. McGowan, Sam D. Kattar, Kevin Wilson, Yudith Garcia, Martin A. Augustin, Charles A. Lesburg, Sanjiv Shah, Peter Goldenblatt, Jason D. Katz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉PI3Kδ mediates key immune cell signaling pathways and is a target of interest for multiple indications in immunology and oncology. Here we report a structure-based scaffold-hopping strategy for the design of chemically diverse PI3Kδ inhibitors. Using this strategy, we identified several scaffolds that can be combined to generate new PI3Kδ inhibitors with high potency and isoform selectivity. In particular, an oxindole-based scaffold was found to impart exquisite selectivity when combined with several hinge binding motifs.〈/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-S0960894X1930530X-ga1.jpg" width="499" 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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Arun K. Ghosh, Jacqueline N. Williams, Satish Kovela, Jun Takayama, Hannah M. Simpson, D. Eric Walters, Shin-ichiro Hattori, Manabu Aoki, Hiroaki Mitsuya〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing a squaramide-derived scaffold as the P2 ligand in combination with a (〈em〉R〈/em〉)-hydroxyethylamine sulfonamide isostere. Inhibitor 〈strong〉3h〈/strong〉 with an 〈em〉N〈/em〉-methyl-3-(〈em〉R〈/em〉)-aminotetrahydrofuranyl squaramide P2-ligand displayed an HIV-1 protease inhibitory K〈em〉〈sub〉i〈/sub〉〈/em〉 value of 0.51 nM. An energy minimized model of 〈strong〉3h〈/strong〉 revealed the major molecular interactions between HIV-1 protease active site and the tetrahydrofuranyl squaramide scaffold that may be responsible for its potent 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-S0960894X19305323-ga1.jpg" width="493" 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 Letters, Volume 29, Issue 18〈/p〉 〈p〉Author(s): Lydia Daniel, Michael P. Gotsbacher, Tomas Richardson-Sanchez, William Tieu, Rachel Codd〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Hydroxamic acid compounds 〈strong〉1〈/strong〉–〈strong〉10〈/strong〉 containing a 〈em〉N〈/em〉-hydroxycinnamamide scaffold and a 4-(benzylamino)methyl cap group that was either unsubstituted (〈strong〉1〈/strong〉) or substituted with one (〈strong〉2〈/strong〉–〈strong〉4〈/strong〉) or two (〈strong〉5〈/strong〉–〈strong〉10〈/strong〉) methoxy groups in variable positions were prepared as inhibitors of Zn(II)-containing histone deacetylases (HDACs). The 3,4- (〈strong〉9〈/strong〉) and 3,5- (〈strong〉10〈/strong〉) bis-methoxy-substituted compounds were the least potent against HeLa nuclear extract, HDAC1 and HDAC2. Molecular modelling showed methoxy groups in the 3-, 4- and 5-position, but not the 2-position, had unfavourable steric interactions with the G32-H33-P34 triad on a loop at the surface of the HDAC2 active site cavity. An HDAC1 homology model showed potential ionic (E243..K288) and cation-pi (K247..F292) interactions between helix 10 and helix 11 that were absent in HDAC2 ((G243..K288) and (K247..V292)). This surface-located interhelical constraint could inform the design of bitopic HDAC1 and HDAC2 selective ligands using an allosteric approach, and/or protein-protein interaction (PPI) 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-S0960894X19305281-ga1.jpg" width="436" 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 Letters〈/p〉 〈p〉Author(s): Geoffroy P.P. Gential, Tim P. Hogervorst, Elena Tondini, Michel J. van de Graaff, Herman S. Overkleeft, Jeroen D.C. Codée, Gijsbert A. van der Marel, Ferry Ossendorp, Dmitri V. Filippov〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Covalent linking of immunogenic oligopeptides with synthetic Toll-like receptor ligands is a useful approach to develop self-adjuvanting vaccines. In particular, small-molecule based agonists of Toll-like receptor 7 (TLR7) that are derived from 8-oxo-adenine core are potentially promising because these chemically robust TLR7 ligands can be connected to peptide T-cell epitopes via straightforward solid-phase peptide synthesis. In this contribution we present the synthesis of a Boc-protected 9-benzyl-2-alkoxy-8-oxo-adenine building block and its application in the online solid phase synthesis of three peptide conjugates that differ in the position of the TLR7 ligand within the peptide. The conjugates are able to induce dendritic cell maturation and T cell proliferation while the position of the ligand impacts T cell proliferation potency.〈/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-S0960894X19302021-ga1.jpg" width="500" 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 Letters〈/p〉 〈p〉Author(s): Michael Webb, Dionisia P. Sideris, Margaret Biddle〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mitochondrial dysfunction is a causative and/or exacerbating feature of many pathologies. We discuss below approaches to modulate mitochondrial dysfunction that involve (1) increasing their energetic efficiency by targeting gene expression regulators such as PPAR or AMPK, (2) using antioxidant compounds to reduce the toxic reactive oxygen species mitochondria produce under stress, or (3) modulating aspects on the innate mitochondrial quality control system. The latter comprise linked processes of biogenesis, dynamic morphological changes, and elimination of defective mitochondria by mitophagy. We discuss representative compounds in all three classes.〈/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-S0960894X19301805-ga1.jpg" width="302" 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 Letters〈/p〉 〈p〉Author(s): John M. Hatcher, Guangyan Du, Lorena Fontán, Ilkay Us, Qi Qiao, Spandan Chennamadhavuni, Jay Shao, Hao Wu, Ari Melnick, Nathanael S. Gray, David A. Scott〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPRfmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that〈/p〉 〈p〉were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.〈/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-S0960894X19301994-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Tao Wang, Owen B. Wallace, Zhongxing Zhang, Haiquan Fang, Zhong Yang, Brett A. Robinson, Timothy P. Spicer, Yi-Fei Gong, Wade S. Blair, Pei-Yong Shi, Pin-Fang Lin, Milind Deshpande, Nicholas A. Meanwell, John F. Kadow〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (〈strong〉3〈/strong〉). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp〈sub〉113〈/sub〉 in gp120, the antiviral potency of several analogues met or exceeded that of 〈strong〉3〈/strong〉, demonstrating that engaging Asp〈sub〉113〈/sub〉 is not a prerequisite for potent antiviral 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-S0960894X19301453-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 Letters〈/p〉 〈p〉Author(s): Yang Yu, Zhicai Wu, Zhi-Cai Shi, Shuwen He, Zhong Lai, Timothy A. Cernak, Petr Vachal, Liu Min, Jian Liu, Qingmei Hong, Tianying Jian, Deodial Guiadeen, Arto Krikorian, Donald M. Sperbeck, Andreas Verras, Lisa M. Sonatore, Beth A. Murphy, Judyann Wiltsie, Christine C. Chung, Judith N. Gorski〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.〈/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-S0960894X19301775-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 Letters〈/p〉 〈p〉Author(s): Liyan Hu, Chuanfang Zhao, Juan Ma, Yang Jing, Yuguo Du〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The binding properties of CD1d/glycolipid/TCR, glycolipid/TCR interactions in particular, have been investigated using docking computation. Accordingly, efficient modification on C-6′ of galactose head was recommended in this report to favor the production of Th2 cytokines. The designed glycolipids have been successfully prepared taking advantages of inverse glycosylation procedure, and their abilities to stimulate mouse iNKT cells 〈em〉in vivo〈/em〉 have been tested. Compound 〈strong〉9〈/strong〉, having 〈em〉p〈/em〉-hydroxyphenylpropionyl amide group on C-6′, presented the best result with respect to the selectivity and quantity on Th2-type cytokine IL-4. We found that the increased glycolipid/TCR interaction might be critical in designing new substrate with Th2-biased cytokine production.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Two α-GalCer analogues were newly designed with the help of docking calculation and efficiently synthesized taking advantages of inverse glycosylation procedure. The prepared compounds exhibited good activity in stimulating mouse iNKT cells 〈em〉in vivo〈/em〉 with a significant Th2 biasing immune response.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19301829-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 Letters〈/p〉 〈p〉Author(s): Hong Lin, Juan I. Luengo〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Protein Arginine Methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 selective inhibitors, 〈strong〉GSK3326595〈/strong〉, a substrate competitive inhibitor, and 〈strong〉JNJ64619178〈/strong〉, a SAM (S-adenosyl-L-methionine) mimetic/competitive inhibitor, have entered clinic trials for multiple cancer types. This review focuses on the recent developments in SAM mimetic nucleoside PRMT5 inhibitors, their SAR and structural insight based on published co-crystal structures.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Ling-Pan Lu, Jin-Hai Liu, Shi-Hong Cen, Ya-Ling Jiang, Guo-Qiang Hu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Lysine specific demethylase (LSD1) plays a pivotal role in epigenetic modulation of gene expression. Abberrant expression of LSD1 was associated with the progress and oncogenesis of multiple human cancers. Herein, we report the preliminary anti-LSD1 evaluation of the synthetic vanadium (V) complexes. Among them, complex 〈strong〉2〈/strong〉 showed a moderate inhibitory effect against LSD1 with IC〈sub〉50〈/sub〉 value of 19.0 μM, as well as good selectivity over MAO-A/B. Complex 〈strong〉2〈/strong〉 is the first vanadium based LSD1 inhibitor, which provides a novel scaffold for the development of LSD1 inhibitor.〈/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-S0960894X18307844-ga1.jpg" width="441" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Daniel G.M. Shore, Zachary K. Sweeney, Alan Beresford, Bryan K. Chan, Huifen Chen, Jason Drummond, Andrew Gill, Tracy Kleinheinz, Xingrong Liu, Andrew D. Medhurst, Edward G. McIver, John G. Moffat, Haitao Zhu, Anthony A. Estrada〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The discovery of disease-modifying therapies for Parkinson’s Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.〈/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-S0960894X18308072-ga1.jpg" width="465" 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 Letters〈/p〉 〈p〉Author(s): Sharon L. Eddie, Aaron Gregson, Emma Graham, Stephanie Burton, Timothy Harrison, Roberta Burden, Christopher J. Scott, Paul B. Mullan, Rich Williams〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for 〈em〉in-vitro〈/em〉 experiments. Our previous research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 〈strong〉2〈/strong〉, a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 〈strong〉16i〈/strong〉, a highly potent inhibitor with excellent physiochemical 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-S0960894X19301581-ga1.jpg" width="500" 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 Letters〈/p〉 〈p〉Author(s): Giorgio Facchetti, Isabella Rimoldi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Starting from the pioneering discovery of picoplatin and phenanthriplatin, many efforts were realized by different research groups in the synthesis of different platinum(II) complexes, bearing a 〈em〉N〈/em〉-heterocycle moiety active as anticancer agents in different types of solid tumors. This review deals in particular with both the bifunctional and monofunctional platinum drugs, not only in dichloride platinum(II) complexes, but also in recent advances in modern platinum structures, i.e. cationic ones. Both the 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 studies of these anticancer agents are taken into account, with a special consideration for aggressive and orphan in treatment tumors.〈/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-S0960894X19301982-ga1.jpg" width="340" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters〈/p〉 〈p〉Author(s): Jinwoo Kim, Mikyung Park, Jiwon Choi, Dileep Kumar Singh, Ho Jeong Kwon, Seong Hwan Kim, Ikyon Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A pyrrolo[1,2-〈em〉a〈/em〉]pyrazine-based chemical territory was expanded via construction of new chemical library with distinctive substitution patterns, which was made possible by regiodivergent electrophilic acylation followed by aldol condensation. Biological screening of the compounds in this class revealed that the viability of human lymphoma U937 cells was strongly inhibited by 〈strong〉6b〈/strong〉 with a methoxy group at the 〈em〉o〈/em〉-position of the aromatic ring, but not by compounds 〈strong〉6t-w〈/strong〉 bearing a halogen at the 〈em〉o〈/em〉-position. Furthermore, 〈strong〉6x〈/strong〉 having a 2,4-dimethoxyphenyl group inhibited the survival of U937 cells more potently than 〈strong〉6b〈/strong〉. In contrast, 〈strong〉6y〈/strong〉 possessing a 2,5-dimethoxyphenyl moiety did not show effective inhibition, implying the importance of orientation of the substituent(s) around the benzene ring. The anticancer action of 〈strong〉6x〈/strong〉 with safe therapeutic window could be associated with the FTase-p38 signaling axis.〈/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-S0960894X19301830-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 Letters〈/p〉 〈p〉Author(s): Gunjan Kashyap, Garima Ameta, Chetna Ameta, Rakshit Ameta, Pinki B. Punjabi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Polyaniline (PANI) and its drug composites with some drugs like Neomycin (NM), Trimethoprim (TMP) and Streptomycin (ST) have been prepared by oxidative polymerization of aniline using hydrochloric acid (HA) and ammonium persulfate (APS) as a dopant and as an oxidant, respectively. The structures of PANI and PANI-drug composites were elucidated by FTIR and NMR spectroscopy, which confirmed the presence of benzenoid and quinoid rings in the synthesized compound. Molecular weight and thermal stability were determined by gel permeation chromatography (GPC) and thermogarvimetric analysis, respectively. From the GPC, PDI values of PANI-NM, PANI-TMP and PANI-ST were found to be 1.37, 1.23 and 1.56, respectively. For the study of antibacterial behavior of the synthesized PANI and PANI-drug composites, different micro-organisms, namely, four Gram positive (〈em〉S. aureus〈/em〉 MTCC 96, 〈em〉B〈/em〉. 〈em〉subtilis〈/em〉 MTCC 441, 〈em〉S. pyogenes〈/em〉 MTCC 442 and 〈em〉S. mutans〈/em〉 MTCC 890) and four Gram negative (〈em〉S. typhi〈/em〉 MTCC 98, 〈em〉KL. pneumoniae〈/em〉 MTCC 109, 〈em〉E. coli〈/em〉 MTCC 443 and 〈em〉P. aeruginosa〈/em〉 MTCC 1688) bacteria were selected due to their pharmacological importance. Some of the PANI-drug composites were found to show excellent results as compared to components polyaniline and drugs used for composite formation. Antituberculosis activity of the PANI and its drug composites against 〈em〉Mycobacterium tuberculosis〈/em〉 H〈sub〉37〈/sub〉RV (acid fast Bacilli) was determined. MIC values for PANI-NM and PANI-TMP were found to be 0.12 and 0.20 µg/mL, respectively. Results suggested that some of the drug composites may be tried as potential candidates for use as an antituberculoid agent to reduce TB transmission.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Synthesis of novel composites of polyaniline with Neomycin, Trimethoprim & Streptomycin and their antibacterial and antituberculosis activity have been reported.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X19301799-ga1.jpg" width="453" 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 Letters〈/p〉 〈p〉Author(s): Yasuha Kusakabe, Shoma Mizutani, Shogo Kamo, Tatsuki Yoshimoto, Shusuke Tomoshige, Tsuneomi Kawasaki, Ryoko Takasawa, Kazunori Tsubaki, Kouji Kuramochi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The antibacterial and cytotoxic activity of seven racemic lactams and both enantiomers of flavipucine were evaluated. Of the compounds tested in this study, flavipucine and phenylflavipucine displayed bactericidal activity against 〈em〉Bacillus subtilis〈/em〉. These results indicate that the pyridione epoxide moiety is a pharmacophore for antibacterial activity against 〈em〉B. subtilis〈/em〉. Flavipucine showed cytotoxic activity against several cancer cells. The cytotoxic activity of flavipucine against human leukemia HL-60 cells is as strong as that of SN-38, the active metabolite of irinotecan. In contrast, the cytotoxic activity of flavipucine against nonneoplastic HEK293 cells and human normal MRC-5 cells is weaker than that of SN-38. No significant differences in the biological activity of the racemates or enantiomers of flavipucine were observed.〈/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-S0960894X19301738-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 Letters〈/p〉 〈p〉Author(s): Alexander J. Nielsen, Sergio Raez-Villanueva, Denis J. Crankshaw, Alison C. Holloway, James McNulty〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The development of aqueous Wittig methodology for the synthesis of α-methylstilbenes using tripropylphosphine-derived phosphonium salts is described. The Wittig olefination reaction was high yielding and allowed isolation of stilbenes by simple filtration and washing with water. The novel phosphonium salts employed were accessed via a highly efficient, regioselective addition of hydrogen bromide to styrenes. Application of the α-methylstilbenes toward the synthesis of a collection of stilbenoid-triazoles is reported and their inhibition of CYP450 19A1 (aromatase) investigated. The overall structure-activity profile provided additional evidence on the aryl halide-ketone bioisostere hypothesis and identified 〈strong〉6c〈/strong〉 as a potent inhibitor of aromatase 〈em〉in vitro〈/em〉 (〈em〉K〈/em〉〈sub〉i〈/sub〉= 8 nM)〈em〉.〈/em〉〈/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-S0960894X19301726-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 Letters〈/p〉 〈p〉Author(s): James G. Taylor, Sheila Zipfel, Kyla Ramey, Randy Vivian, Adam Schrier, Kapil K. Karki, Ashley Katana, Darryl Kato, Tetsuya Kobayashi, Ruben Martinez, Michael Sangi, Dustin Siegel, Chinh V. Tran, Zheng-Yu Yang, Jeff Zablocki, Cheng Y. Yang, Yujin Wang, Kelly Wang, Katie Chan, Ona Barauskas〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Treatment of Hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi ® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral 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-S0960894X19301787-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 Letters〈/p〉 〈p〉Author(s): Samer S. Daher, Xiao Jin, Jimmy Patel, Joel S. Freundlich, Bettina Buttaro, Rodrigo B. Andrade〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Novel antibacterial drugs that treat multidrug resistant pathogens are in high demand. We have synthesized analogs of solithromycin using Cu(I)-mediated click chemistry. Evaluation of the analogs using Minimum Inhibitory Concentration (MIC) assays against resistant 〈em〉Staphylococcus aureus, Escherichia coli〈/em〉, and multidrug resistant pathogens 〈em〉Enterococcus faecium〈/em〉 and 〈em〉Acinetobacter baumannii〈/em〉 showed they possess potencies similar to those of solithromycin, thus demonstrating their potential as future therapeutics to combat the existential threat of multidrug resistant pathogens.〈/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-S0960894X19301763-ga1.jpg" width="401" 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 Letters〈/p〉 〈p〉Author(s): Aleksandar Radakovic, Dale L. Boger〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In recent efforts, several C20’ urea vinblastine analogues were discovered that displayed remarkable potency against vinblastine-sensitive tumor cell lines (IC〈sub〉50〈/sub〉 50–75 pM), being roughly 100-fold more potent than vinblastine, and that exhibited decreased susceptibility to Pgp efflux-derived resistance in a vinblastine-resistant cell line. Their extraordinary activity indicate that it is not likely or even possible that their cellular functional activity is derived from stoichiometric occupancy of the intracellular tubulin binding sites. Rather, their potency indicates sub-stoichiometric or even catalytic occupancy of candidate binding sites may be sufficient to disrupt tubulin dynamics or microtubule assembly during mitosis. We detail efforts to delineate the underlying behavior responsible for the increased potency and show that the ultra-potent extended C20’ ureas retain the mechanistic behavior of vinblastine, display enhanced affinity for tubulin and on-target activity approximately 100-fold both in vitro and in HeLa cells, but do not show evidence of catalytic disassembly of microtubulin. We also use the analogues to show that, in live interphase cells, the effects of the vinblastine class of drugs do not display a catastrophic effect on the microtubule skeleton, but rather a subtler insult to its dynamicity, acting as sub-stoichiometic drugs that inhibit normal microtublin maturation and dynamics.〈/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-S0960894X19301751-ga1.jpg" width="236" 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 Letters〈/p〉 〈p〉Author(s): Sandeep Rana, Mourad Bendjennat, Smit Kour, Hannah M. King, Smitha Kizhake, Muhammad Zahid, Amarnath Natarajan〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.〈/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-S0960894X1930174X-ga1.jpg" width="467" 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 Letters〈/p〉 〈p〉Author(s): Yumeng Zhang, Minlong Wang, Maqsood Ahmed, Lu He, Mingshan Ji, Zhiqiu Qi, Xinghai Li〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉To develop more valuable and effective fungicide candidates, a novel series of 3,4-dichloroisothioxazole-based cycloalkylsulfonamides were synthesized and their structures were identified by 〈sup〉1〈/sup〉H NMR, 〈sup〉13〈/sup〉C NMR, MS and elemental analysis. Compound 〈strong〉3k〈/strong〉 was further confirmed by X-ray single crystal diffraction. The in vitro bioassay results demonstrated that the target compounds showed significant fungicidal activity on mycelial growth and spore germination of 〈em〉Botrytis cinerea〈/em〉. Especially, compound 〈strong〉3j〈/strong〉, with prominent inhibition effect on mycelial with EC〈sub〉50〈/sub〉 and EC〈sub〉80〈/sub〉 values of 1.4 and 23.7 μg/mL respectively, was comparable to the selected commercial fungicide. Moreover, at 50 μg/mL, the inhibition rate of compound 〈strong〉3j〈/strong〉 on spore germination was recorded up to 89.7%. The further in vivo bioassay results indicated compound 〈strong〉3j〈/strong〉 continued to show high control effect on tomato leaves, flowers and fruit at 200 μg/mL, with control effeciencies of 94.3%, 89.3% and 91.9%, respectively. The structure-activity relationship showed that the compound with a five-membered ring possessed the best activity after the introduction of the active fragment of the 3,4-dichloroisothioxazole, provided a valuable idea for further creation of new fungicides.〈/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-S0960894X19302008-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Wakana Ishioka, Sayaka Oonuki, Takehiro Iwadate, Ken-ichi Nihei〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Resorcinol alkyl glucosides 〈strong〉7〈/strong〉–〈strong〉12〈/strong〉 were developed as novel tyrosinase inhibitors based on the structure of rhododendrin. These were synthesized from 2,4-dibenzyloxybenzaldehyde using either the Wittig or the Horner-Wadsworth-Emmons reaction with Koenigs-Knorr glycosylation as key steps. The tyrosinase inhibitory activity of 〈strong〉7〈/strong〉–〈strong〉12〈/strong〉 increased with the length of the alkyl spacer between resorcinol and glucose. The 50% inhibitory concentration (IC〈sub〉50〈/sub〉) of tetradecyl derivative 〈strong〉12〈/strong〉 was 0.39 μM, making it the most potent of the compounds synthesized. The IC〈sub〉50〈/sub〉 of 〈strong〉8〈/strong〉 (3.62 μM) with a propyl spacer was ca 10 times that of 〈strong〉7〈/strong〉 (35.9 μM) with an ethyl spacer. This significant activity difference suggests that an interaction between resorcinol alkyl glucoside and tyrosinase may increase remarkably if the length of the alkyl spacer exceeds C〈sub〉3〈/sub〉.〈/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-S0960894X18308965-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Xiana Qian, Shuangzhan Zhang, Shuyuan Xue, Wuyu Mao, Minqiu Xu, Weipan Xu, Hexin Xie〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Reported herein is a fluorescence assay for the rapid screening of metallo-β-lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem 〈strong〉CPC-1〈/strong〉 as substrate and is compatible with all MBLs, including B1, B2 and B3 subclass MBLs. The efficiency of this assay was demonstrated by the rapid inhibition screening of a number of molecules against B2 MBL CphA and 2,3-dimercaprol was identified as a potent CphA inhibitor.〈/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-S0960894X18308874-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Robert A. Mook, Jiangbo Wang, Xiu-Rong Ren, Hailan Piao, H. Kim Lyerly, Wei Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide’s inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin 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-S0960894X18308886-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Pilju Choi, Kwantae Kim, Taejung Kim, Young-Tae Park, Bong Geun Song, Myoung-Sook Shin, Yong Ho Kim, Gwi Seo Hwang, Ki Sung Kang, Jungyeob Ham〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉To increase the contents of medicinally effective ginsenosides, we used high-temperature and high-pressure thermal processing of ginseng by exposing it to microwave irradiation. To determine the anti-melanoma effect, the malignant melanoma SK-MEL-2 cell line was treated with an extract of microwave-irradiated ginseng. Microwave irradiation caused changes in the ginsenoside contents: the amounts of ginsenosides Rg1, Re, Rb1, Rb2, Rc, and Rd were disappeared, while those of less polar ginsenosides, such as Rg3, Rg5, and Rk1, were increased. In particular, the contents of Rk1 and Rg5 markedly increased. Melanoma cells treated with the microwave-irradiated ginseng extract showed markedly increased cell death. The results indicate that the microwave-irradiated ginseng extract induced melanoma cell death via the apoptotic pathway and that the cytotoxic effect of the microwave-irradiated ginseng extract is attributable to the increased contents of specific ginsenosides.〈/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-S0960894X18309788-ga1.jpg" width="269" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Nicholas C. Schumann, John Bruning, Andrew C. Marshall, Andrew D. Abell〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A series of dipeptide aldehydes containing different 〈em〉N〈/em〉-terminal heterocycles was prepared and assayed 〈em〉in vitro〈/em〉 against α-chymotrypsin to ascertain the importance of the heterocycle in maintaining a β-strand geometry while also providing a hydrogen bond donor equivalent to the backbone amide nitrogen of the surrogate amino acid. The dipeptide containing a pyrrole constraint (〈strong〉10〈/strong〉) was the most potent inhibitor, with 〉30-fold improved activity over dipeptides which lacked a nitrogen hydrogen bond donor (namely thiophene 〈strong〉11〈/strong〉, furan 〈strong〉12〈/strong〉 and pyridine 〈strong〉13〈/strong〉). Molecular docking studies of 〈strong〉10〈/strong〉 bound to α-chymotrypsin demonstrates a hydrogen bond between the pyrrole nitrogen donor and the backbone carbonyl of Gly〈sub〉216〈/sub〉 located in the S〈sub〉3〈/sub〉 pocket which is proposed to be critical for overall binding.〈/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-S0960894X18309806-ga1.jpg" width="244" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Shengchao Li, Bo Wu, Weiping Zheng〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In the current study, two cyclic tripeptides respectively harboring a thiourea-type and a carboxamide-type of catalytic mechanism-based sirtuin inhibitory warheads as the central residue were found to behave as potent (low μM level) inhibitors against the tRNA-activated human SIRT7 deacetylase activity. Despite exhibiting a potent pan-inhibition against the deacylase activities of the five tested human sirtuins (i.e. SIRT1/2/3/6/7), these two compounds represent the first examples of potent SIRT7 inhibitors ever identified thus far, and their identification could facilitate the future development of more potent and selective SIRT7 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-S0960894X18309570-ga1.jpg" width="366" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Tanja Grkovic, Jason R. Evans, Rhone K. Akee, Liang Guo, Myrtle Davis, Johnson Jato, Paul G. Grothaus, Michelle Ahalt-Gottholm, Melinda Hollingshead, Jerry M. Collins, David J. Newman, Barry R. O'Keefe〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Two new cassaine-type diterpenoids, namely erythrofordins D (〈strong〉1〈/strong〉) and E (〈strong〉2〈/strong〉), sourced from a Cameroon collection of 〈em〉Erythrophleum suaveolens〈/em〉 were isolated and assessed for anti-tumor activity. In the NCI-60 cancer cell assay, erythrofordins D (〈strong〉1〈/strong〉) and E (〈strong〉2〈/strong〉) were found to be cytotoxic in the low micro molar ranges with a mean GI〈sub〉50〈/sub〉 value of 2.45 and 0.71 µM, mean TGI value of 9.77 and 2.29 µM, and a mean LC〈sub〉50〈/sub〉 of 26.92 and 11.48 µM for 〈strong〉1〈/strong〉 and 〈strong〉2〈/strong〉 respectively. Using the COMPARE algorithm, the new compounds were found to have similar NCI-60 response profiles to the known cardiac glycosides hyrcanoside and strophanthin. In addition, in an assay examining the viability and contractile function in human cardiomyocytes derived from induced pluripotent stem-cells, erythrofordins showed cardiotoxicity effects at concentrations as low as 0.03 µg/mL.〈/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-S0960894X18309533-ga1.jpg" width="233" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Jiho Song, Soyeon Jang, Jung Wuk Lee, Danbee Jung, Seul Lee, Kyung Hoon Min〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Discovery of mutant-selective kinase inhibitors is one of the challenges in medicinal chemistry and is a main issue for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. We tried to improve the selectivity of pan-HER inhibitors for mutant EGFRs. Utilizing click chemistry, triazole-tethered quinazoline derivatives were synthesized, based on a quinazoline scaffold showing pan-HER inhibition. The representative compound 〈strong〉5j〈/strong〉 exhibited 17- and 52-fold improved selectivity for EGFR L858R/T790M over wild-type EGFR and HER2, respectively, and demonstrated 6.7-fold more potent antiproliferative activity against PC9 cells harboring EGFR-activating mutation than gefitinib. Although the described quinazolines did not surpass pyrimidines as 3rd generation EGFR inhibitors in terms of selectivity for mutant EGFRs, our approach might provide information that would help in the identification of mutant-selective compounds among pan-HER inhibitors using the quinazoline scaffold.〈/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-S0960894X18309545-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Claude Barberis, James Pribish, Elina Tserlin, Alexandre Gross, Mark Czekaj, Matthieu Barragué, Paul Erdman, Sachin Maniar, John Jiang, Luke Fire, Vinod Patel, Andrew Hebert, Mikhail Levit, Anlai Wang, Frank Sun, Shih-Min A. Huang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉〈em〉N〈/em〉-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 〈strong〉17〈/strong〉 showed tumor growth inhibition in a KG1 tumor-bearing mouse 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-S0960894X18309491-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Tomoyuki Tanaka, Nana Yajima, Tomoko Kiyoshi, Yoshiki Miura, Yoshifumi Inoue, Takuya Nishimaki, Seiji Iwama〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉By further optimizing compound 〈strong〉A〈/strong〉 [2′-fluoro-〈em〉N〈/em〉-methyl-[1,1′-biphenyl]-2-sulfonamide], we identified 〈strong〉DSP-0565〈/strong〉 [2-(2′-fluoro-[1,1′-biphenyl]-2-yl)acetamide, 〈strong〉17a〈/strong〉] as a strong, broad-spectrum anti-epileptic drug (AED) candidate. Our efforts mainly focused on finding an alternative polar group for the sulfonamide in order to improve ADME profile of compound 〈strong〉A〈/strong〉 including good metabolic stability and no reactive metabolic production. This led to the identification of biphenyl acetamide as a new scaffold for development of broad-spectrum AED candidates. 〈strong〉DSP-0565〈/strong〉 showed anti-convulsant activity in various models (scPTZ, MES, 6 Hz and amygdala kindling) with good safety margin, and was therefore selected as a clinical candidate.〈/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-S0960894X1830948X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Yong-Jin Wu, Brian Venables, Jason Guernon, Jie Chen, Sing-Yuen Sit, Ramkumar Rajamani, Ronald J. Knox, Michele Matchett, Rick L. Pieschl, James Herrington, Linda J. Bristow, Nicholas A. Meanwell, Lorin A. Thompson, Carolyn Dzierba〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 〈strong〉6〈/strong〉 as a potent Na〈sub〉v〈/sub〉1.7 inhibitor. Replacement of the C2 furanyl ring of 〈strong〉6〈/strong〉 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNa〈sub〉v〈/sub〉1.7 IC〈sub〉50〈/sub〉 values under 50 nM. Fluorine substitution of the truncated compound 〈strong〉12〈/strong〉 led to 〈strong〉34〈/strong〉 with improved potency and isoform selectivity. The inverted indole 〈strong〉36〈/strong〉 also maintained good activity. Both 〈strong〉34〈/strong〉 and 〈strong〉36〈/strong〉 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Na〈sub〉v〈/sub〉1.7 inhibitors to treat pain.〈/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-S0960894X18309478-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Yong Guo, Jiangping Fan, Qian Zhang, Chongnan Bao, Zhiyan Liu, Ruige Yang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉To improve the insecticidal activities of fraxinellone, two series of fraxinellone-based 〈em〉N〈/em〉-(1,3-thiazol-2-yl)carboxamides containing 25 compounds were prepared by structural modification. Their structures were determined by melting point, optical rotation, IR, 〈sup〉1〈/sup〉H NMR and ESI-MS. The steric configurations of compounds 〈strong〉6i〈/strong〉, 〈strong〉7d〈/strong〉 and 〈strong〉7i〈/strong〉 were unambiguously confirmed by X-ray diffraction further. The bioassay showed that compounds 〈strong〉6b〈/strong〉 and 〈strong〉6i〈/strong〉 exhibited more potent larvicidal and growth inhibitory activities against 〈em〉Plutella xylostella〈/em〉 Linnaeus and 〈em〉Mythimna separata〈/em〉 Walker, respectively. Moreover, compounds 〈strong〉6b〈/strong〉 and 〈strong〉6i〈/strong〉 also displayed low cytotoxicity to noncancerous mammalian cells. The structure–activity relationships (SARs) of all target compounds were also observed.〈/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-S0960894X18309363-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Marcus J.C. Long, Ann P. Lawson, Rick Baggio, Yu Qian, Lior Rozhansky, Domenico Fasci, Farid El Oualid, Eranthie Weerapana, Lizbeth Hedstrom〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Promiscuous inhibitors of tyrosine protein kinases, proteases and phosphatases are useful reagents for probing regulatory pathways and stabilizing lysates as well as starting points for the design of more selective agents. Ubiquitination regulates many critical cellular processes, and promiscuous inhibitors of deubiquitinases (DUBs) would be similarly valuable. The currently available promiscuous DUB inhibitors are highly reactive electrophilic compounds that can crosslink proteins. Herein we introduce diarylcarbonate esters as a novel class of promiscuous DUB inhibitors that do not have the liabilities associated with the previously reported compounds. Diarylcarbonates stabilize the high molecular weight ubiquitin pools in cells and lysates. They also elicit cellular phenotypes associated with DUB inhibition, demonstrating their utility in ubiquitin discovery. Diarylcarbonates may also be a useful scaffold for the development of specific DUB 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-S0960894X18309314-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Cheng Shang See, Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, Sang Hyun Lee, Brian W. Dymock〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A131 (〈strong〉1〈/strong〉) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 〈strong〉1〈/strong〉. SAR studies of 〈strong〉1〈/strong〉 indicate that only the specific structure of 〈strong〉1〈/strong〉 elicits the full pharmacological effect. However, application of 〈strong〉1〈/strong〉 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 〈strong〉1〈/strong〉 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 〈strong〉10〈/strong〉, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.〈/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-S0960894X18309284-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Saniya Virani, Zhongxing Liang, Younghyoun Yoon, Hyunsuk Shim, Suazette R. Mooring〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100 nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 〈strong〉3l〈/strong〉, 〈strong〉7f〈/strong〉, 〈strong〉7j〈/strong〉, and 〈strong〉7p〈/strong〉 show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist.〈/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-S0960894X18309296-ga1.jpg" width="268" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Nan Zheng, Qun Hao, Kuaile Lin, Jing Pan, Yingxia Li, Weicheng Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉A new series of 1-substituted pyrazolopyrimidine derivatives were synthesized as potent BTK inhibitors and they were evaluated by enzyme-based assay and anti-proliferation against multiple B-cell lymphoma cell lines 〈em〉in vitro〈/em〉. Among these compounds, 〈strong〉9h〈/strong〉 exhibited the highest potency against BTK enzyme, with IC〈sub〉50〈/sub〉 value of 4.2 nM. In particular, 〈strong〉8〈/strong〉 and 〈strong〉9f〈/strong〉 performed better inhibition against the proliferation of B lymphoma cell lines DOHH2 and WSU-DLCL2 than the clinical drug ibrutinb. In addition, the test toward the normal PBMC cells showed that 〈strong〉8〈/strong〉 possessed low cell cytotoxicity. All these explorations indicated that 〈strong〉8〈/strong〉 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment.〈/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-S0960894X18309272-ga1.jpg" width="425" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): Xiao Ding, Luigi Piero Stasi, Xuedong Dai, Kai Long, Cheng Peng, Baowei Zhao, Hailong Wang, Changhui Sun, Huan Hu, Zehong Wan, Karamjit S. Jandu, Oliver J. Philps, Yan Chen, Lizhen Wang, Qian Liu, Colin Edge, Yi Li, Kelly Dong, Xiaoming Guan, F. David Tattersall〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 〈strong〉18〈/strong〉 and 〈strong〉23〈/strong〉, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 〈strong〉18〈/strong〉 proved to be brain penetrant, and the high unbound fraction of compound 〈strong〉18〈/strong〉 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.〈/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-S0960894X18309302-ga1.jpg" width="182" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Ruolan Zhou, Shaoyu Fang, Minmin Zhang, Qingsen Zhang, Jian Hu, Mingping Wang, Chongqing Wang, Ju Zhu, Aijun Shen, Xin Chen, Canhui Zheng〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 〈strong〉7e〈/strong〉–〈strong〉7g〈/strong〉 showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstracts〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X18309983-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Steven P. Govek, Celine Bonnefous, Jackaline D. Julien, Johnny Y. Nagasawa, Mehmet Kahraman, Andiliy G. Lai, Karensa L. Douglas, Anna M. Aparicio, Beatrice D. Darimont, Katherine L. Grillot, James D. Joseph, Joshua A. Kaufman, Kyoung-Jin Lee, Nhin Lu, Michael J. Moon, Rene Y. Prudente, John Sensintaffar, Peter J. Rix, Jeffrey H. Hager, Nicholas D. Smith〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor 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-S0960894X18309892-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Xiaoqing Ye, Rukang Zhang, Fulin Lian, Weiyao Zhang, Wenchao Lu, Jie Han, Naixia Zhang, Jia Jin, Cheng Luo, Kaixian Chen, Fei Ye, Hong Ding〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The protein-protein interaction between WDR5 (WD40 repeat protein 5) and MLL1 (mixed-lineage leukemia 1) is important for maintaining optimal H3K4 methyltransferase activity of MLL1. Dysregulation of MLL1 catalytic function is relevant to mixed-lineage leukemia, and targeting WDR5-MLL1 interaction could be a promising therapeutic strategy for leukemia harboring MLL1 fusion proteins. To date, several peptidomimetic and non-peptidomimetic small-molecule inhibitors targeting WDR5-MLL1 interaction have been reported, yet the discovery walk of new drugs inhibiting MLL1 methytransferase activity is still in its infancy. It’s urgent to find other small-molecule WDR5-MLL1 inhibitors with novel scaffolds. In this study, through fluorescence polarization (FP)-based high throughput screening, several small-molecule inhibitors with potent inhibitory activities 〈em〉in vitro〈/em〉 against WDR5-MLL1 interaction were discovered. Nuclear Magnetic Resonance (NMR) assays were carried out to confirm the direct binding between hit compounds and WDR5. Subsequent similarity-based analog searching of the 4 hits led to several inhibitors with better activity, among them, DC_M5_2 displayed highest inhibitory activity with IC〈sub〉50〈/sub〉 values of 9.63 ± 1.46 µM. Furthermore, a molecular docking study was performed and disclosed the binding modes and interaction mechanisms between two most potent inhibitors and WDR5.〈/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-S0960894X1830982X-ga1.jpg" width="329" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 1 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 3〈/p〉 〈p〉Author(s): Christian Harcken, Daniel Kuzmich, Brain Cook, Can Mao, Darren Disalvo, Hossein Razavi, Alan Swinamer, Pingrong Liu, Qiang Zhang, Alison Kukulka, Donna Skow, Mita Patel, Monica Patel, Kimberly Fletcher, Tara Sherry, David Joseph, Dustin Smith, Melissa Canfield, Donald Souza, Matthew Bogdanffy〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 〈strong〉6〈/strong〉 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 〈strong〉19e〈/strong〉 that was advanced to early clinical trials.〈/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-S0960894X18309582-ga1.jpg" width="381" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Ben Acton, Helen F. Small, Kate M. Smith, Alison McGonagle, Alexandra I.J. Stowell, Dominic I. James, Niall M. Hamilton, Nicola Hamilton, James R. Hitchin, Colin P. Hutton, Ian D. Waddell, Donald J. Ogilvie, Allan M. Jordan〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve 〈em〉in vivo〈/em〉 half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected 〈em〉in vivo〈/em〉 toxicity which was attributed to this single-atom modification.〈/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-S0960894X18310278-ga1.jpg" width="468" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Lijun Li, Ruizhe Li, Yumei Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The overexpression of lysine specific demethylase 1 (LSD1) has been reported in various human tumors. There is increasing interest in targeting LSD1 with small molecules for cancer treatment. A released structure of an LSD1 kinase domain in complex with FAD was used to set up a low-cost high-throughput docking protocol for quick identification of LSD1 inhibitors. The most promising hit 〈strong〉L05〈/strong〉 was confirmed to be a potent, selective and reversible LSD1 inhibitor and displayed marked inhibition of colorectal cells migration without significant cytotoxicity.〈/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-S0960894X18310291-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Mario Contin, Claudia Sepúlveda, Mirta Fascio, Carlos A. Stortz, Elsa B. Damonte, Norma B. D'Accorso〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉In this work, several ribavirin analogues were synthesized and incorporated into a multivalent arrangement. Both were subsequently modified by the addition of polyhydroxylated residues.〈/p〉 〈p〉Their antiviral activity was tested against Junín virus, etiological agent responsible of Argentine hemorrhagic fever.〈/p〉 〈p〉Some compounds inhibited Junín virus in the range of 13.2–389.1 µM. Two modified ribavirin analogues presented an effective concentration comparable to ribavirin but with a higher selectivity index.〈/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-S0960894X18310254-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 15 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 2〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Chae Jo Lim, Nam Hui Kim, Hye Jin Park, Byung Ho Lee, Kwang-Seok Oh, Kyu Yang Yi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 〈strong〉1〈/strong〉, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 〈strong〉1y〈/strong〉 as a highly potent UT antagonist with an IC〈sub〉50〈/sub〉 value of 6 nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉The synthesis and SAR of 5-arylfuran-2-carboxamide derivatives as urotensin-II receptor antagonists are described.〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0960894X18310059-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Description: 〈p〉Publication date: 15 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry Letters, Volume 29, Issue 4〈/p〉 〈p〉Author(s): Christophe D. Guillon, Yi-Hua Jan, Natalie Foster, Joel Ressner, Diane E. Heck, Jeffrey D. Laskin, Ned D. Heindel〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Linear furocoumarins, also known as psoralens, are clinically useful photo-activated pharmaceuticals employed to address hyperproliferative skin diseases. Seven diverse cytotoxic pharmacophores have been synthetically attached to 8-methoxypsoralen via a 5-amino functionality. The resulting unique set of compounds was evaluated for dark and light toxicity against PAM212 keratinocytes in culture.〈/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-S0960894X18309958-ga1.jpg" width="302" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉