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

Hezhen Wang, Bader Huwaimel, Kshitij Verma, James Miller, Todd M Germain, Nihar Kinarivala, Dimitri Pappas, Paul S Brookes, Paul C Trippier

ChemMedChem 2017 Jul 06

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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. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Hezhen Wang, Bader Huwaimel, Kshitij Verma, James Miller, Todd M Germain, Nihar Kinarivala, Dimitri Pappas, Paul S Brookes, Paul C Trippier. Synthesis and Antineoplastic Evaluation of Mitochondrial Complex II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin A5. ChemMedChem. 2017 Jul 06;12(13):1033-1044