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

Maksims Yevglevskis; Amit Nathubhai; Katty Wadda; Guat L Lee; Suzanne Al-Rawi; Tingying Jiao; Paul J Mitchell; Tony D James; Michael D Threadgill; Timothy J Woodman; Matthew D Lloyd

doi:10.1016/j.bioorg.2019.103263

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

Maksims Yevglevskis, Amit Nathubhai, Katty Wadda, Guat L Lee, Suzanne Al-Rawi, Tingying Jiao, Paul J Mitchell, Tony D James, Michael D Threadgill, Timothy J Woodman, Matthew D Lloyd^*

^*Corresponding author for this work

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Research output: Contribution to Journal › Article › peer-review

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.

Original language	English
Pages (from-to)	103263
Number of pages	8
Journal	Bioorganic Chemistry
Volume	92
Early online date	7 Sept 2019
DOIs	https://doi.org/10.1016/j.bioorg.2019.103263
Publication status	Published - 1 Nov 2019

Bibliographical note

Keywords

Antineoplastic Agents/chemical synthesis
Cell Line, Tumor
Cell Proliferation/drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors/chemical synthesis
Humans
Male
Molecular Structure
Prostatic Neoplasms/drug therapy
Racemases and Epimerases/antagonists & inhibitors
Structure-Activity Relationship

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bioorg.2019.103263

https://www.sciencedirect.com/science/article/pii/S0045206819304365

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Yevglevskis, M., Nathubhai, A., Wadda, K., Lee, G. L., Al-Rawi, S., Jiao, T., Mitchell, P. J., James, T. D., Threadgill, M. D., Woodman, T. J., & Lloyd, M. 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. https://doi.org/10.1016/j.bioorg.2019.103263

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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.",

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AU - Yevglevskis, Maksims

AU - Nathubhai, Amit

AU - Wadda, Katty

AU - Lee, Guat L

AU - Al-Rawi, Suzanne

AU - Jiao, Tingying

AU - Mitchell, Paul J

AU - James, Tony D

AU - Threadgill, Michael D

AU - Woodman, Timothy J

AU - Lloyd, Matthew D

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AB - 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.

KW - Antineoplastic Agents/chemical synthesis

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Dose-Response Relationship, Drug

KW - Drug Screening Assays, Antitumor

KW - Enzyme Inhibitors/chemical synthesis

KW - Humans

KW - Male

KW - Molecular Structure

KW - Prostatic Neoplasms/drug therapy

KW - Racemases and Epimerases/antagonists & inhibitors

KW - Structure-Activity Relationship

U2 - 10.1016/j.bioorg.2019.103263

DO - 10.1016/j.bioorg.2019.103263

M3 - Article

C2 - 31536953

SN - 0045-2068

VL - 92

SP - 103263

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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