Cytotoxic Indolocarbazoles from Actinomadura melliaura ATCC 39691

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• 作者：Khaled A. Shaaban ; Sherif I. Elshahawi ; Xiachang Wang ; Jamie Horn ; Madan K. Kharel ; Markos Leggas ; Jon S. Thorson
• 刊名：Journal of Natural Products
• 出版年：2015
• 出版时间：July 24, 2015
• 年：2015
• 卷：78
• 期：7
• 页码：1723-1729
• 全文大小：449K
• ISSN：1520-6025

文摘

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鈥?b>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鈥?b>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.