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Novel 2-arylthiopropanoyl-CoA inhibitors of α-methylacyl-CoA racemase 1A (AMACR; P504S) as potential anti-prostate cancer agents

Authors :
P J Mitchell
Matthew D. Lloyd
Tony D. James
Michael D. Threadgill
Suzanne Al-Rawi
Timothy J. Woodman
Maksims Yevglevskis
Tingying Jiao
Guat Ling Lee
Katty Wadda
Amit Nathubhai
Source :
Jevglevskis, M, Nathubhai, A, Wadda, K, Lee, G L, Al-Rawi, S, Jiao, T, Mitchell, P, James, T, Threadgill, M, Woodman, T & Lloyd, M 2019, ' Novel 2-arylthiopropanoyl-CoA inhibitors of α-methylacyl-CoA racemase 1A (AMACR; P504S) as potential anti-prostate cancer agents ', Bioorganic Chemistry, vol. 92, 103263 . https://doi.org/10.1016/j.bioorg.2019.103263
Publication Year :
2019

Abstract

α-Methylacyl-CoA racemase (AMACR; P504S) catalyses an essential step in the degradation of branched-chain fatty acids and the activation of ibuprofen and related drugs. AMACR has gained much attention as a drug target and biomarker, since it is found at elevated levels in prostate cancer and several other cancers. Herein, we report the synthesis of 2-(phenylthio)propanoyl-CoA derivatives which provided potent AMACR inhibitory activity (IC50 = 22–100 nM), as measured by the AMACR colorimetric activity assay. Inhibitor potency positively correlates with calculated logP, although 2-(3-benzyloxyphenylthio)propanoyl-CoA and 2-(4-(2-methylpropoxy)phenylthio)propanoyl-CoA were more potent than predicted by this parameter. Subsequently, carboxylic acid precursors were evaluated against androgen-dependent LnCaP prostate cancer cells and androgen-independent Du145 and PC3 prostate cancer cells using the MTS assay. All tested precursor acids showed inhibitory activity against LnCaP, Du145 and PC3 cells at 500 µM, but lacked activity at 100 µM. This is the first extensive structure-activity relationship study on the influence of side-chain interactions on the potency of novel rationally designed AMACR inhibitors.

Details

ISSN :
10902120 and 00452068
Volume :
92
Database :
OpenAIRE
Journal :
Bioorganic chemistry
Accession number :
edsair.doi.dedup.....e4f9f4749ac6c14930709969dec8e052
Full Text :
https://doi.org/10.1016/j.bioorg.2019.103263