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

Yevglevskis, Maksims, Nathubhai, Amit, Wadda, Katty, Lee, Guat, Al-Rawi, Suzanne, Jiao, Tingying, Mitchell, Paul, J., James, Tony, D., Threadgill, Michael, D., Woodman, Timothy, J. and Lloyd, Matthew, D. (2019) Novel 2-arylthiopropanoyl-CoA inhibitors of α-methylacyl-CoA racemase 1A (AMACR; P504S) as potential anti-prostate cancer agents. Bioorganic Chemistry, 92 (103263). pp. 1-8. ISSN 0045-2068

[img]
Preview
PDF
Nathubhai.Amit AAM Novel 2-arylthiopropanoyl-CoA.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (652kB) | Preview

Search Google Scholar

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 structureactivity relationship study on the influence of side-chain interactions on the potency of novel rationally designed AMACR inhibitors.

Item Type: Article
Subjects: Sciences > Chemistry
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
Related URLs:
Depositing User: Amit Nathubhai
Date Deposited: 19 Sep 2019 10:12
Last Modified: 05 Sep 2020 02:38
URI: http://sure.sunderland.ac.uk/id/eprint/11122
ORCID for Amit Nathubhai: ORCID iD orcid.org/0000-0003-3686-2799

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year