Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

[thumbnail of Discovery of deshydroxy bicalutamide derivatives as androgen receptor antagonists.pdf]
PDF - Accepted Post-Print Version
Download (2MB) | Preview


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
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 13 February 2019
Date of Acceptance: 22 January 2019
Last Modified: 26 Aug 2021 09:28

Citation Data

Cited 7 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics