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

Abstract

The enzyme alpha-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 alpha-methylacyl coenzyme A esters, possessing one or more beta-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 microM and are the most potent inhibitors yet known. The presence of beta-fluorine on the alpha-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 alpha-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. alpha-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.

• Authors: Andrew J Carnell, Ian Hale, Simone Denis, Ronald J A Wanders, William B Isaacs, Brice A Wilson, Sacha Ferdinandusse
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 11 Pg. 2700-7 (May 31 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17477519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acyl Coenzyme A
• Antineoplastic Agents
• Myristates
• alpha-trifluoromethyltetradecanoic acid
• alpha-trifluoromethyltetradecanoyl-CoA
• Racemases and Epimerases
• alpha-methylacyl-CoA racemase

Topics

• Acyl Coenzyme A (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Cell Proliferation (drug effects)
• Crystallography, X-Ray
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Male
• Myristates (chemical synthesis, chemistry, pharmacology)
• Prostatic Neoplasms
• Racemases and Epimerases (antagonists & inhibitors, chemistry)
• Stereoisomerism