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

ChemMedChem
Hezhen WangPaul C Trippier

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.

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Citations

Jan 1, 2019·PloS One·Nicole Melo CalixtoLourival de Almeida Silva
Aug 17, 2020·ELife·Chaitanya A KulkarniPaul S Brookes
Aug 23, 2020·International Journal of Molecular Sciences·Luca FrattaruoloAnna Rita Cappello
Oct 14, 2020·Royal Society Open Science·Adejoke OsinubiOluwole Familoni
Dec 18, 2020·ChemMedChem·Bader I HuwaimelPaul C Trippier
May 5, 2020·Journal of the American Chemical Society·Undramaa Bat-ErdeneYi Tang
Jul 21, 2020·Journal of Medicinal Chemistry·Shikha KumariPaul C Trippier
Aug 27, 2021·Journal of Medicinal Chemistry·Md Shafikur RahmanPaul C Trippier
Oct 1, 2021·ChemMedChem·Luke R OdellAdam McCluskey

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