Actinomadura melliaura ATCC 39691, a strain isolated from a soil sample collected in Bristol Cove, California, is a known producer of the disaccharide-substituted AT2433 indolocarbazoles (6-9). Reinvestigation of this strain using new media conditions led to >40-fold improvement in the production of previously reported AT2433 metabolites and the isolation and structure elucidation of the four new analogues, AT2433-A3, A4, A5, and B3 (1-4). The availability of this broader set of compounds enabled a subsequent small antibacterial/fungal/cancer SAR study that revealed disaccharyl substitution, N-6 methylation, and C-11 chlorination as key modulators of bioactivity. The slightly improved anticancer potency of the newly reported N-6-desmethyl 1 (compared to 6) contrasts extensive SAR of monoglycosylated rebeccamycin-type topoisomerase I inhibitors where N-6 alkylation has contributed to improved potency and ADME. Complete 2D NMR assignments for the known metabolite BMY-41219 (5) and (13)C NMR spectroscopic data for the known analogue AT2433-B1 (7) are also provided for the first time
cytotoxicity, indolocarbazoles, Actinomadura melliaura
NCBI PubMed ID: 26091285Publication DOI: 10.1021/acs.jnatprod.5b00429Journal NLM ID: 7906882Publisher: American Society of Pharmacognosy
Correspondence: jsthorson@uky.edu
Institutions: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, USA, Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, USA, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, USA
Methods: 13C NMR, 1H NMR, NMR-2D, TLC, HPLC, UV, extraction, SEC, CC, cell growth, HPLC-MS, HR-ESI-MS, cell viability assay, evaporation, antimicrobial assay
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