Cytotoxic Indolocarbazoles from Actinomadura melliaura ATCC 39691

Abstract

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.

Figure 1

Chemical structures of indolopyrrolocarbazoles 1–11.

Figure 2

¹H–¹H–COSY and selected HMBC correlations for indolocarbazoles 1–4.

Figure 3

Key NOESY correlations for indolocarbazoles 1, 2, and 4.

Figure 4

Viability of PC3 (prostate), A549 (lung), and U118 (brain) human cancer cell lines at 10 μM treatment for compounds 1–7 after 72 h (see Supporting Information, Table S1).