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

32 Citations (Scopus)

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

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Bacilli
Biological Products
Bacillus
Oxazines
Alkaloids
Biosynthesis
Receptor Protein-Tyrosine Kinases
Cell growth
Fibroblasts
Cytotoxicity
Cells
Nuclear magnetic resonance
X rays
Inhibitory Concentration 50
Cell Movement
Lung Neoplasms
Cell Proliferation
X-Rays
Cell Line
discoipyrrole A

ASJC Scopus subject areas

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

Cite this

Discoipyrroles A-D : Isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis. / Hu, Youcai; Potts, Malia B.; Colosimo, Dominic; Herrera-Herrera, Mireya L.; Legako, Aaron G.; Yousufuddin, Muhammed; White, Michael A.; MacMillan, John B.

In: Journal of the American Chemical Society, Vol. 135, No. 36, 11.09.2013, p. 13387-13392.

Research output: Contribution to journalArticle

Hu, Youcai ; Potts, Malia B. ; Colosimo, Dominic ; Herrera-Herrera, Mireya L. ; Legako, Aaron G. ; Yousufuddin, Muhammed ; White, Michael A. ; MacMillan, John B. / Discoipyrroles A-D : Isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis. In: Journal of the American Chemical Society. 2013 ; Vol. 135, No. 36. pp. 13387-13392.
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