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Discovery of deshydroxy bicalutamide derivatives as androgen receptor antagonists

Kandil, Sahar, Lee, Kok Yung, Davies, Laurie, Rizzo, Sebastiano A., Dart, D. Alwyn and Westwell, Andrew D. 2019. Discovery of deshydroxy bicalutamide derivatives as androgen receptor antagonists. European Journal of Medicinal Chemistry 167 , pp. 49-60. 10.1016/j.ejmech.2019.01.054
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Abstract

Deshydroxy propioanilides were synthesised by Michael addition reaction between substituted thiophenols onto four different phenylacrylamide derivatives to give twenty-three novel deshydroxy bicalutamide derivatives lacking the central hydroxyl group. The antiproliferative activities of these compounds were evaluated against human prostate cancer cell lines and thirteen compounds showed better inhibitory activities (IC50 = 2.67–13.19 μM) compared to bicalutamide (IC50 = 20.44 μM) in LNCaP. Remarkably, novel double branched bicalutamide analogues (27 and 28) were isolated as major by-products and found to have the best activity across three human prostate cancer cell lines (LNCaP, VCaP and PC3). The most active compound 28 shows sub-micromolar activity (IC50 = 0.43 μM in LNCaP), which represents more than 40-fold improvement over the clinical anti-androgen bicalutamide (IC50 = 20.44 μM) and a more than 3 fold improvement over enzalutamide (IC50 = 1.36 μM). Moreover, strong reduction of PSA expression in LNCaP cells upon treatment with compounds 27, 28 and 33 was observed during qPCR analysis, confirming their AR antagonist activity. Molecular modelling studies revealed a novel binding mode of these structurally distinct double branched analogues within the ligand binding domain (LBD) of the androgen receptor.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Medicine
Psychology
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 13 February 2019
Date of Acceptance: 22 January 2019
Last Modified: 22 Feb 2019 14:00
URI: http://orca.cf.ac.uk/id/eprint/119479

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