TY - JOUR
T1 - Discoipyrroles A-D
T2 - Isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis
AU - Hu, Youcai
AU - Potts, Malia B.
AU - Colosimo, Dominic
AU - Herrera-Herrera, Mireya L.
AU - Legako, Aaron G.
AU - Yousufuddin, Muhammed
AU - White, Michael A.
AU - MacMillan, John B.
PY - 2013/9/11
Y1 - 2013/9/11
N2 - 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.
AB - 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.
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U2 - 10.1021/ja403412y
DO - 10.1021/ja403412y
M3 - Article
C2 - 23984625
AN - SCOPUS:84884171796
SN - 0002-7863
VL - 135
SP - 13387
EP - 13392
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 36
ER -