ALBERT

Description: Chemical investigation of the marine sponge Ircinia oros yielded four linear furanosesterterpenoids, including the known metabolites ircinin-1 (1) and ircinin-2 (2) and two new compounds, ircinialactam E (3) and ircinialactam F (4). Their chemical structures were elucidated by using a combination of [α]D, NMR, HRMS, and FT-IR spectroscopy. The absolute configuration of C-18 in compounds 1–3 was identified as R by electronic circular dichroism (ECD) spectroscopy coupled with time-dependent density functional theory calculations. Compounds 1–4 showed moderate leishmanicidal, trypanocidal, and antiplasmodial activities (IC50 values 28–130 μM). This is the second report of rare glycinyl lactam derivatives 3 and 4 from the genus Ircinia.

Description: Chemical investigation of the marine bryozoan Flustra foliacea collected in Iceland resulted in isolation of 13 new bromotryptamine alkaloids, flustramines Q-W (1-7) and flustraminols C-H (8-13), and two new imidazole alkaloids, flustrimidazoles A and B (14 and 15), together with 12 previously described compounds (16-27). Their structures were established by detailed spectroscopic analysis using 1D and 2D NMR and HRESIMS. Structure 2 was verified by calculations of the 13C and 1H NMR chemical shifts using density functional theory. The relative and absolute configurations of the new compounds were elucidated on the basis of coupling constant analysis, NOESY, [α]D, and ECD spectroscopic data, in addition to chemical derivatization. The compounds were tested for in vitro anti-inflammatory activity using a dendritic cell model. Eight compounds (1, 3, 5, 13, 16, 18, 26, and 27) decreased dendritic cell secretion of the pro-inflammatory cytokine IL-12p40, and two compounds (4 and 14) increased secretion of the anti-inflammatory cytokine IL-10. Deformylflustrabromine B (27) showed the most potent anti-inflammatory effect (IC50 2.9 μM). These results demonstrate that F. foliacea from Iceland expresses a broad range of brominated alkaloids, many without structural precedents. The potent anti-inflammatory activity in vitro of metabolite 27 warrants further investigations into its potential as a lead for inflammation-related diseases.

Description: Guided by LC-MS/MS molecular networking-based metabolomics and cytotoxic activity, two new discorhabdin-type alkaloids, tridiscorhabdin (1) and didiscorhabdin (2), were isolated from the sponge Latrunculia biformis, collected from the Weddell Sea (Antarctica) at -291 m depth. Their structures were established by HRESIMS, NMR, [α]D, and ECD data coupled with DFT calculations. Both compounds bear a novel C-N bridge (C-1/N-13) between discorhabdin monomers, and 1 represents the first trimeric discorhabdin molecule isolated from Nature. Tridiscorhabdin (1) exhibited strong cytotoxic activity against the human colon cancer cell line HCT-116 (IC50 value 0.31 μM).

Description: Pathologic hyperreactive inflammatory responses occur when there is excessive activation of a proinflammatory NF-kappa B pathway and a reduced cytoprotective NRF2 cascade. The noncytotoxic, highly selective COX-2 inhibitory flavonol-enriched butanol fraction (UaB) from Uvaria alba (U. alba) was investigated for its inflammatory modulating potential by targeting NF-kappa B activation and NRF2 activity. Enzyme-linked immunosorbent assay was initially performed to measure levels of proinflammatory mediators [nitric oxide (NO), prostaglandin E2, and reactive oxygen species (ROS)] and cytokines [tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, and IL-6], followed by reverse transcription-polymerase chain reaction and western blotting to determine mRNA and protein expression, respectively. Using immunofluorescence staining combined with western blot analysis, the activation of NF-kappa B was further investigated. NRF2 activity was also measured using a luciferase reporter assay. UaB abrogated protein and mRNA expressions of inducible nitric oxide synthase (iNOS), COX-2, TNF-alpha, IL-1 beta, and IL-6 in RAW 264.7 macrophages, thereby suppressing the production of proinflammatory mediators and cytokines. This was further validated when a concentration-dependent decrease in NO and ROS production was observed in zebrafish (Danio rerio) larvae. UaB also increased NRF2 activity in HaCaT/ARE cell line and attenuated NF-kappa B activation by inhibiting the nuclear translocation of transcription factor p65 in RAW 264.7 macrophages. Nontargeted LC- MS analysis of UaB revealed the presence of the flavonols quercitrin (1), quercetin (2), rutin (3), kaempferol (4), and kaempferol 3O-rutinoside (5). Molecular docking indicates that major flavonol aglycones have high affinity toward COX-2 NSAID-binding sites, TNF-alpha, and TNF-alpha converting enzyme, while the glycosylated flavonoids showed strong binding toward iNOS and IKK-all possessing dynamic stability when performing molecular dynamics simulations at 140 ns. This is the first report to have elucidated the mechanistic anti-inflammatory potential of the Philippine endemic plant U. alba.

Description: Inhibition of the major cyclic adenosine monophosphate- metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. As a springboard to explore new anti-cancer and anti-Alzheimer's chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species Uvaria alba using in vitro assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of U. alba elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profiling analysis of the bioactive extract identified 18 putative secondary metabolites. Molecular docking and molecular dynamics simulations showed strong free energy binding mechanisms and dynamic stability at 50- ns simulations in the catalytic domains of PDE4 B2B, ubiquitin-specific peptidase 14, and Kelch-like ECH-associated protein 1 (KEAP-1 Kelch domain) for the benzylated dihydroflavone dichamanetin (16), and of an AChE and KEAP-1 BTB domain for 3- (3,4-dihydroxybenzyl)-3',4',6-trihydroxy-2,4-dimethoxychalcone (8) and grandifloracin (15), respectively. Density functional theory calculations to demonstrate Michael addition reaction of the most electrophilic metabolite and kinetically stable grandifloracin (15) with Cys151 of the KEAP-1 BTB domain illustrated favorable formation of a β-addition adduct. The top-ranked compounds also conferred favorable in silico pharmacokinetic properties.

Description: Vatairea guianenis Aubl. (Fabaceae) is an Amazonian medicinal plant species traditionally used for treating skin diseases. In an initial screening, a V. guianensis leaf extract and its subextracts showed antibacterial and antifungal activities. The EtOAc subextract was selected for chemical workup and afforded five known (1–4 and 8) and six undescribed isoflavones, vatairenones C–H (5–7 and 9–11). All isoflavones are prenylated in position C-8, displaying either chain-prenylated (1–7) or ring-closed forms (8–11). The most bioactive compound (3) exhibited in vitro activity against clinically relevant bacteria and fungi with IC50 values ranging from 6.8 to 26.9 μM. Due to its broad antimicrobial activity and low general toxicity, compound 3 is a potential lead compound for structural modifications. The results of the present study support the ethnomedicinal use of V. guianensis in the treatment of dermatological disorders. 1H NMR spectra of some of the isolated compounds showed intricate signal patterns, which might explain repeated errors in assigning the correct structure of the isoflavonoid B-ring in the literature and which we resolved by higher order spectra simulations.

Description: Certain cyanobacteria of the secondary metabolite-rich order Nostocales can establish permanent symbioses with a large number of cycads, by accumulating in their coralloid roots and shifting their metabolism to dinitrogen fixation. Here, we report the discovery of two new lipoglycopeptides, desmamides A (1) and B (2), together with their aglycone desmamide C (3), from the nostocalean cyanobacterium Desmonostoc muscorum LEGE 12446 isolated from a cycad (Cycas revoluta) coralloid root. The chemical structures of the compounds were elucidated using a combination of 1D and 2D NMR spectroscopy and mass spectrometry. The desmamides are decapeptides featuring O-glycosylation of tyrosine (in 1 and 2) and an unusual 3,5-dihydroxy-2-methyldecanoic acid residue. The biosynthesis of the desmamides was studied by substrate incubation experiments and bioinformatics. We describe herein the dsm biosynthetic gene cluster and propose it to be associated with desmamide production. The discovery of this class of very abundant (〉1.5% d.w.) bacterial lipoglycopeptides paves the way for exploration of their potential role in root endosymbiosis.

Description: Onychomycosis caused by, e.g., Trichophyton rubrum or Candida albicans is the most common human nail disease with a worldwide prevalence of more than 10%. The therapeutic efficacy of topical antimycotics for the treatment of onychomycosis proved to be inadequate in numerous studies on patients. The main reasons are, above all, the poor bioavailability of the active ingredients in the nail compartment, causing the requirement for extremely long application periods and correspondingly high demands on adherence by the patient. In the present study, we aimed to develop a more effective and prompt photodynamic approach for the treatment of onychomycosis. The principle of photodynamic therapy (PDT) for onychomycosis has already been investigated. However, these studies used photosensitizers such as methylene blue, which were neither optimized for their keratinophilic features nor for their bioavailability in the nail. Hence, we initiated a screening campaign using T. rubrum and C. albicans cell-based assays, infected bovine keratin models, and keratin-penetrating irradiation to identify suitable hit compounds for a PDT approach toward onychomycosis. Here, we report on the discovery of Henna/Lawson-derived keratinophilic naphthazarines that act as highly potent PDT antimycotic photosensitizers with photoresponsiveness when irradiated by light at a keratin-permeable wavelength (〉500 nm, e.g., compounds 10 and 11 with PDT-IC50 = 1 and 3 nM, respectively, against T. rubrum), hence with superior efficacy than the positive controls nystatin and clotrimazole. Notably, our photodynamic approach not only affected the actual pathogens but also prevented reinfection of keratin models within 10 days, suggesting an additional efficacy against fungal spores. Compared to established concepts, our proposed PDT approach using the novel naphthazarine photosensitizers could enable an effective, precise, and sustainable therapy option for the future treatment of onychomycosis.