期刊
CHEMMEDCHEM
卷 12, 期 13, 页码 1033-1044出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700196
关键词
anticancer agents; atpenin A5; mitochondria; mitochondrial complex II; succinate dehydrogenase
资金
- Texas Tech University Health Sciences Center School of Pharmacy
- Kingdom of Saudi Arabia Cultural Mission to the USA
- US National Institutes of Health [R01-HL071158]
Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogues of the CII inhibitor natural product atpenin A5 were prepared to evaluate the structure-activity relationship of the C5 pyridine side chain. The side chain ketone moiety was determined to be pharmacophoric, engendering a bioactive conformation. One analogue, 1-(2,4-dihydroxy-5,6-dimethoxypyridin-3-yl) hexan-1-one (16c), was found to have a CII IC50 value of 64 nm, to retain selectivity for CII over mitochondrial complex I (>156-fold), and to possess a ligand-lipophilicity efficiency (LLE) of 5.62, desirable metrics for a lead compound. This derivative and other highly potent CII inhibitors show potent and selective anti-proliferative activity in multiple human prostate cancer cell lines under both normoxia and hypoxia, acting to inhibit mitochondrial electron transport.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据