Synthesis and Antineoplastic Evaluation of Mitochondrial Complex?II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin?A5.

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 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.

SUBMITTER: Wang H 

PROVIDER: S-EPMC5557372 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature