期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 36, 页码 13387-13392出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja403412y
关键词
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资金
- US National Institutes of Health [R01 CA149833, RC2 CA148225, U01 CA176284]
- Welch Foundation [I-1689]
- Komen for the Cure Postdoctoral Fellowship
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,S-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.
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