Discoipyrroles A-D: Isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis

Youcai Hu, Malia B. Potts, Dominic Colosimo, Mireya L. Herrera-Herrera, Aaron G. Legako, Muhammed Yousufuddin, Michael A. White, John B. MacMillan

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variety of cellular response pathways, including regulation of cell growth, proliferation, and motility. Using a newly developed platform to identify the signaling pathway/molecular target of natural products, we identified a family of alkaloid natural products, discoipyrroles A-D (1-4), from Bacillus hunanensis that inhibit the DDR2 signaling pathway. The structure of 1-4, determined by detailed two-dimensional (2D) NMR methods and confirmed by X-ray crystallographic analysis has an unusual 3H-benzo[d]pyrrolo][1,3]oxazine-3,5- dione core. Discoipyrroles A-D potently inhibit DDR2 dependent migration of BR5 fibroblasts and show selective cytotoxicity to DDR2 mutant lung cancer cell lines (IC50 120-400 nM). Examination of the biosynthesis has led to the conclusion that the discoipyrroles are formed through a nonenzymatic process, leading to a one-pot total synthesis of 1.

Original languageEnglish (US)
Pages (from-to)13387-13392
Number of pages6
JournalJournal of the American Chemical Society
Volume135
Issue number36
DOIs
StatePublished - Sep 11 2013

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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