Bhole Ritesh P, Chikhale Rupesh V, Wavhale Ravindra D, Asmary Fatmah Ali, Almutairi Tahani Mazyad, Alhajri Hassna Mohammed, Bonde Chandrakant G
Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, Maharashtra, India.
Division of Pharmacy and Optometry, University of Manchester, Manchester, UK.
Heliyon. 2021 Mar 8;7(3):e06227. doi: 10.1016/j.heliyon.2021.e06227. eCollection 2021 Mar.
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 () for synthesis. All the compounds were evaluated 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 (, IC - 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 (, IC - 18.26 to 20.31μM) were successful with promising 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 studies. It provided strong theoretical support to our hypothesis.
雄激素受体抑制剂恩杂鲁胺已被证明对去势抵抗性前列腺癌有效，在男性患者中显示出临床益处并提高了生存率。然而，AR突变（F876L）使恩杂鲁胺从拮抗剂转变为激动剂，这表明耐药性迅速演变。因此，我们的目标是通过设计和开发新型恩杂鲁胺类似物来克服这种耐药机制。我们利用恩杂鲁胺的形状和静电特征设计了一个恩杂鲁胺衍生物数据集，以匹配与雄激素受体紧密结合所必需的药效团特征。基于此设计策略，选择了十种新型衍生物，包括5,5-二甲基-3-(6-取代苯并[d]噻唑/恶唑-2-基)-2-硫代-1-(4-(三氟甲基)吡啶-2-基)咪唑啉-4-酮（）用于合成。所有化合物均在前列腺癌细胞系DU-145、LNCaP和PC3上进行了评估。有趣的是，两种化合物3-(6-羟基苯并[d]噻唑-2-基)-5,5-二甲基-2-硫代-1-(4-(三氟甲基)吡啶-2-基)咪唑啉-4-酮（，IC - 18.26至20.31μM）和3-(6-羟基苯并[d]恶唑-2-基)-5,5-二甲基-2-硫代-1-(4-(三氟甲基)吡啶-2-基)咪唑啉-4-酮（，IC - 18.26至20.31μM）成功地对前列腺癌细胞系具有有前景的抗增殖活性。通过分子对接、分子动力学模拟和MM-GBSA结合自由能计算进一步研究了潜在雄激素受体抑制剂的结合机制，结果与研究一致。这为我们的假设提供了有力的理论支持。
