Design, synthesis, and in vitro testing of alpha-methylacyl-CoA racemase inhibitors.
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.
Carnell
Andrew J
AJ
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom. acarnell@liv.ac.uk
Hale
Ian
I
Denis
Simone
S
Wanders
Ronald J A
RJ
Isaacs
William B
WB
Wilson
Brice A
BA
Ferdinandusse
Sacha
S
D000214:Acyl Coenzyme A / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D009226:Myristates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism
D000214:Acyl Coenzyme A; D000970:Antineoplastic Agents; D009226:Myristates; C520848:alpha-trifluoromethyltetradecanoic acid; C520849:alpha-trifluoromethyltetradecanoyl-CoA; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase