Cytotoxic Indolocarbazoles from Actinomadura melliaura ATCC 39691
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 13C NMR spectroscopic data for the known analogue AT2433-B1 (7) are also provided for the first time.
Shaaban KA, Elshahawi SI, Wang X, et al. Cytotoxic indolocarbazoles from Actinomadura melliaura ATCC 39691. J Nat Prod. 2015;78(7):1723-1729. https://doi.org/10.1021/acs.jnatprod.5b00429
American Chemical Society and American Society of Pharmacognosy