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Novel 2-arylthiopropanoyl-CoA inhibitors of α-methylacyl-CoA racemase 1A (AMACR; P504S) as potential anti-prostate cancer agents
- 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.
- Subjects :
- Male
Carboxylic acid
Racemases and Epimerases
Drug design
Antineoplastic Agents
urologic and male genital diseases
01 natural sciences
Biochemistry
Prostate cancer
Structure-Activity Relationship
DU145
SDG 3 - Good Health and Well-being
Cell Line, Tumor
Drug Discovery
LNCaP
medicine
Potency
Humans
Enzyme Inhibitors
Molecular Biology
Cell Proliferation
sub_chemistry
chemistry.chemical_classification
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
Prostatic Neoplasms
medicine.disease
Ibuprofen
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Cancer research
Biomarker (medicine)
Drug Screening Assays, Antitumor
medicine.drug
Subjects
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