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Synthesis and Antineoplastic Evaluation of Mitochondrial Complex II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin A5
Author(s) -
Wang Hezhen,
Huwaimel Bader,
Verma Kshitij,
Miller James,
Germain Todd M.,
Kinarivala Nihar,
Pappas Dimitri,
Brookes Paul S.,
Trippier Paul C.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700196
Subject(s) - moiety , lipophilicity , stereochemistry , chemistry , natural product , succinate dehydrogenase , selectivity , mitochondrion , ketone , pyridine , biochemistry , combinatorial chemistry , medicinal chemistry , organic chemistry , catalysis
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.