Design, synthesis, and in vitro testing of α-methylacyl-CoA racemase inhibitors

Andrew J. Carnell, Ian Hale, Simone Denis, Ronald J.A. Wanders, William B. Isaacs, Brice A. Wilson, Sacha Ferdinandusse

Research output: Contribution to journalArticle

Abstract

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 pK a 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.

Original languageEnglish (US)
Pages (from-to)2700-2707
Number of pages8
JournalJournal of medicinal chemistry
Volume50
Issue number11
DOIs
StatePublished - May 31 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Carnell, A. J., Hale, I., Denis, S., Wanders, R. J. A., Isaacs, W. B., Wilson, B. A., & Ferdinandusse, S. (2007). Design, synthesis, and in vitro testing of α-methylacyl-CoA racemase inhibitors. Journal of medicinal chemistry, 50(11), 2700-2707. https://doi.org/10.1021/jm0702377