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Design, Synthesis, and In Vitro Testing of α-Methylacyl-CoA Racemase Inhibitors

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journal contribution
posted on 31.05.2007, 00:00 by Andrew J. Carnell, Ian Hale, Simone Denis, Ronald J. A. Wanders, William B. Isaacs, Brice A. Wilson, Sacha Ferdinandusse
The enzyme α-methylacyl-CoA racemase (AMACR) is overexpressed in prostate, colon, and other cancers and has been partially validated as a potential therapeutic target by siRNA knockdown of the AMACR gene. Analogs of the natural substrate branched chain α-methylacyl coenzyme A esters, possessing one or more β-fluorine atoms, have been synthesized using Wittig, conjugate addition, and asymmetric aldol reactions and found to be reversible competitive inhibitors. Each diastereomer of the previously reported inhibitor ibuprofenoyl-CoA was also tested. The compounds had Ki values of 0.9−20 μM and are the most potent inhibitors yet known. The presence of β-fluorine on the α-methyl group or the acyl chain results in a significant lowering of the Ki value compared with nonfluorinated analogs, and this is attributed to a lowering of the pKa of the α-proton, facilitating enolization and binding. Several of the CoA ester inhibitors were formed by incubating the free carboxylic acid precursors with cell free extracts and CoA. α-Trifluoromethyltetradecanoic acid, the precursor to the most potent inhibitor, was shown to inhibit growth of cancer cell lines PC3, CWR22 Rv1, and Du145 in a dose-dependent manner and could be related to the expression level of AMACR.