Cytotoxic Indolocarbazoles from Actinomadura melliaura ATCC 39691

Khaled A. Shaaban, Sherif I. Elshahawi, Xiachang Wang, Jamie Horn, Madan K. Kharel, Markos Leggas, Jon S. Thorson

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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 13C NMR spectroscopic data for the known analogue AT2433-B1 (7) are also provided for the first time. (Chemical Equation Presented).

Original languageEnglish
Pages (from-to)1723-1729
Number of pages7
JournalJournal of Natural Products
Volume78
Issue number7
DOIs
StatePublished - Jul 24 2015

Bibliographical note

Publisher Copyright:
© 2015 The American Chemical Society and American Society of Pharmacognosy.

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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