1. Cytotoxic Indolocarbazoles from Actinomadura melliaura ATCC 39691.
- Author
-
Shaaban KA, Elshahawi SI, Wang X, Horn J, Kharel MK, Leggas M, and Thorson JS
- Subjects
- Antibiotics, Antineoplastic chemistry, Antibiotics, Antineoplastic pharmacology, California, Carbazoles chemistry, Humans, Indole Alkaloids chemistry, Microbial Sensitivity Tests, Micrococcus luteus drug effects, Molecular Structure, Mycobacterium smegmatis drug effects, Nuclear Magnetic Resonance, Biomolecular, Saccharomyces cerevisiae drug effects, Soil Microbiology, Staphylococcus aureus drug effects, Topoisomerase I Inhibitors chemistry, Actinomycetales chemistry, Antibiotics, Antineoplastic isolation & purification, Carbazoles isolation & purification, Carbazoles pharmacology, Indole Alkaloids isolation & purification, Indole Alkaloids pharmacology, Topoisomerase I Inhibitors isolation & purification, Topoisomerase I Inhibitors pharmacology
- 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.
- Published
- 2015
- Full Text
- View/download PDF