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

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 , IC 50 – 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 , IC 50 – 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.

Assessment of critical impact of superbugs in human health: A known beyond

“…They are frequently employed in combination regimens because of this. 31 Antibiotics found in nature can target a wide range of organisms. Antibacterial peptides are the most common type of natural antimicrobial agent and are found in almost all species.…”

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

“…As discussed in this review, specific AR mutations not only confer resistance to antiandrogens (such as enzalutamide) but can also convert these compounds in AR agonists, indicating a rapid development of drug resistance. In recent papers, by means of molecular docking and molecular dynamics simulations, novel AR antagonists were developed and found to exert a significant antitumor effect in CRPC cells as well as in PCa cells engineered to overexpressed the F876L mutant AR [ 298 , 299 ]. Moreover, a full characterization of AR mutations, achieved by genomic studies, will likely increase the treatment options for CRPC patients, in terms of personalized therapy.…”

Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

“…Recently, numerous small molecules bearing diversified heterocyclic scaffolds have been proved as potential anticancer agents via different mechanisms, including inhibition of angiogenesis and/or cell apoptosis induction 17 . For the meantime, the bicyclic isosteric scaffolds, namely; benzothiazole, benzoxazole and benzimidazole are considered as vital leads for many pharmacological activities including anti-inflammatory 25–29 , antiviral 30–33 , and mainly antitumor 34–45 . As a privileged scaffold, benzothiazole was the main nucleus for several compounds, such as compound DF-203 ( Figure 1 ) that showed significant in-vitro anticancer activities.…”