Novel 2-arylthiopropanoyl-CoA inhibitors of α-methylacyl-CoA racemase 1A (AMACR; P504S) as potential anti-prostate cancer agents
| Autor: | 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 |
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| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | 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 |
| ISSN: | 1090-2120 0045-2068 |
| DOI: | 10.1016/j.bioorg.2019.103263 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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