Discoipyrroles A-D: Isolation, Structure Determination, and Synthesis of Potent Migration Inhibitors from Bacillus hunanensis

作者：Hu Youcai; Potts Malia B; Colosimo Dominic; Herrera Herrera Mireya L; Legako Aaron G; Yousufuddin Muhamrned; White Michael A; MacMillan John B^*

来源：Journal of the American Chemical Society, 2013, 135(36): 13387-13392.

DOI：10.1021/ja403412y

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.

• 出版日期2013-9-11