Pyrromycin

DNA methyltransferase inhibitors (DNMTis) have become an alternative for cancer therapies. However, only two DNMTis have been approved as anticancer drugs, although with some restrictions. Natural products (NPs) are a promising source of drugs. In order to find NPs with novel chemotypes as DNMTis, 47 compounds with known activity against these enzymes were used to build a LDA-based QSAR model for active/inactive molecules (93% accuracy) based on molecular descriptors. This classifier was employed to identify potential DNMTis on 800 NPs from NatProd Collection. 447 selected compounds were docked on two human DNA methyltransferase (DNMT) structures (PDB codes: 3SWR and 2QRV) using AutoDock Vina and Surflex-Dock, prioritizing according to their score values, contact patterns at 4 Å and molecular diversity. Six consensus NPs were identified as virtual hits against DNMTs, including 9,10-dihydro-12-hydroxygambogic, phloridzin, 2',4'-dihydroxychalcone 4'-glucoside, daunorubicin, pyrromycin and centaurein. This method is an innovative computational strategy for identifying DNMTis, useful in the identification of potent and selective anticancer drugs.

Acquisition of Actinobacteria, especially Streptomyces from previously underexplored habitats and the exploration of their biosynthetic potential have gained much attention in the rejuvenated antibiotics search programs. Herein, we isolated some Streptomyces strains, from an arid region of the Great Indian Thar Desert, which possess an ability to produce novel bioactive compounds. Twenty-one morphologically distinctive strains differing in their aerial and substrate mycelium were isolated by employing a stamping method. Among them, 12 strains were identified by a two-level antimicrobial screening method, exerting antimicrobial effects against a panel of indicator strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus species. Based on their potent antimicrobial activity, four isolates were further explored by 16S rRNA gene-based identification, genetic screening, and metabolomic analysis; and it was found that these strains belong to the genus Streptomyces. The selected strains were found to have polyketide synthase and non-ribosomal peptide synthetase systems. In addition, extracellular metabolomic screening revealed that the isolates produced analogs of doxorubicinol, pyrromycin, erythromycin, and 6-13 other putative novel metabolites. These results demonstrate the significance of Streptomyces inhabiting the arid region of Thar Desert, suggesting that similar arid environments can be considered as the reservoirs of novel Streptomyces strains that could have biotechnological significance.

The ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that directly contributes to high-density lipoprotein (HDL) biogenesis by mediating the cellular efflux of cholesterol and phospholipids to lipid-poor apolipoprotein A-I. Therefore, identification of a novel upregulator of ABCA1 would be beneficial for atherosclerosis prevention and/or therapy because of its pivotal role in cholesterol homeostasis and HDL metabolism. In this study, a high-throughput assay method for ABCA1 upregulators was developed and used for screening a synthetic and natural compound library. The cell-based high-throughput screen is conducted in a 96-well format using the human hepatoma HepG2 cells stably transfected with ABCA1 promoter-luciferase construct and calibrated with reference ABCA1 upregulators (oxysterols, 9-cis-retinoic acid, thiazolidinediones, cyclic adenosine monophosphate, verapamil, fenofibrate, and oncostatin M). Among 2600 compounds, 4 microbial compounds (pyrromycin, aclarubicin, daidzein, and pratensein) were picked up as hits by the high-throughput screening assay, and those compounds were further identified as upregulators of ABCA1 expression by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis.