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Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents

Bhole, RP; Chikhale, RV; Wavhale, RD; Asmary, FA; Almutairi, TM; Alhajri, HM; Bonde, CG; (2021) Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents. Heliyon , 7 (3) , Article e06227. 10.1016/j.heliyon.2021.e06227. Green open access

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Abstract

The androgen receptor inhibitor, Enzalutamide, proved effective against castration resistance prostate cancer, has demonstrated clinical benefits and increased survival rate in men. However, AR mutation (F876L) converts Enzalutamide from antagonist to agonist indicating a rapid evolution of resistance. Hence, our goal is to overcome this resistance mechanism by designing and developing novel Enzalutamide analogues. We designed a dataset of Enzalutamide derivatives using Enzalutamide's shape and electrostatic features to match with pharmacophoric features essential for tight binding with the androgen receptor. Based on this design strategy ten novel derivatives were selected including 5,5-dimethyl-3-(6-substituted benzo[d]thia/oxazol-2-yl)-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl)imidazolidin-4-one (6a-j) for synthesis. All the compounds were evaluated in-vitro on prostate cancer cell lines DU-145, LNCaP and PC3. Interestingly, two compounds 3-(6-hydroxybenzo[d]thiazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl) imidazolidin-4-one (6c, IC50 – 18.26 to 20.31μM) and 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl -2-thioxo- 1- (4-(trifluoromethyl) pyridin-2-yl)imidazolidin-4-one (6h, IC50 – 18.26 to 20.31μM) were successful with promising in-vitro antiproliferative activity against prostate cancer cell lines. The binding mechanism of potential androgen receptor inhibitors was further studied by molecular docking, molecular dynamics simulations and MM-GBSA binding free energy calculations and found in agreement with the in vitro studies. It provided strong theoretical support to our hypothesis. Hybrid molecules; Prostate cancer; Imidazolidinone derivatives; Molecular docking; Molecular dynamics simulations; Binding energy calculations.

Type: Article
Title: Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.heliyon.2021.e06227
Publisher version: https://doi.org/10.1016/j.heliyon.2021.e06227
Language: English
Additional information: This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync- nd/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/10124564
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