部分
亲脂性
立体化学
化学
天然产物
琥珀酸脱氢酶
选择性
线粒体
酮
吡啶
生物化学
组合化学
药物化学
有机化学
催化作用
作者
Hezhen Wang,Bader Huwaimel,Kshitij Verma,James H. Miller,Todd Germain,Nihar Kinarivala,Dimitri Pappas,Paul S. Brookes,Paul C. Trippier
出处
期刊:ChemMedChem
[Wiley]
日期:2017-06-12
卷期号:12 (13): 1033-1044
被引量:41
标识
DOI:10.1002/cmdc.201700196
摘要
Abstract 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 ( 16 c ), was found to have a CII IC 50 value of 64 n m , 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.
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