Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):880-896. doi: 10.1080/14756366.2020.1740692.
Abnormal alterations in the expression and biological function of retinoid X receptor alpha (RXRα) have a key role in the development of cancer. Potential modulators of RXRα as anticancer agents are explored in growing numbers of studies. A series of (4/3-(pyrimidin-2-ylamino)benzoyl)hydrazine-1-carboxamide/carbothioamide derivatives are synthesised and evaluated for anticancer activity as RXRα antagonists in this study. Among all synthesised compounds, shows strong antagonist activity (half maximal effective concentration (EC) = 1.68 ± 0.22 µM), potent anti-proliferative activity against human cancer cell lines HepG2 and A549 cells (50% inhibition of cell viability (IC) values < 10 µM), and low cytotoxic property in normal cells such as LO2 and MRC-5 cells (IC values > 100 µM). Further bioassays indicate that inhibits 9-cis-RA-induced activity in a dose-dependent manner, and selectively binds to RXRα-=LΒD with submicromolar affinity (Kd = 1.20 × 10 M). induces time-and dose-dependent cleavage of poly ADP-ribose polymerase, and significantly stimulates caspase-3 activity, leading to RXRα-dependent apoptosis. Finally, molecular docking studies predict the binding modes for RXRα-LBD and .
视黄醇 X 受体 α（RXRα）的表达和生物学功能的异常改变在癌症的发展中起着关键作用。越来越多的研究探索了 RXRα 作为抗癌剂的潜在调节剂。在本研究中，我们合成了一系列（4/3-（嘧啶-2-基氨基）苯甲酰基）肼-1-甲酰胺/碳二酰胺衍生物，并评估了它们作为 RXRα 拮抗剂的抗癌活性。在所合成的所有化合物中，化合物 表现出很强的拮抗剂活性（半最大有效浓度（EC）= 1.68 ± 0.22 μM），对人肝癌细胞系 HepG2 和 A549 细胞具有很强的抗增殖活性（50%抑制细胞活力（IC）值<10 μM），对正常细胞如 LO2 和 MRC-5 细胞的细胞毒性较低（IC 值>100 μM）。进一步的生物测定表明，化合物 以剂量依赖的方式抑制 9-顺式-RA 诱导的活性，并选择性地与 RXRα-LBD 以亚微摩尔亲和力结合（Kd = 1.20×10−6 M）。化合物 诱导聚 ADP-核糖聚合酶的时间和剂量依赖性切割，并显著刺激 caspase-3 活性，导致 RXRα 依赖性细胞凋亡。最后，分子对接研究预测了 RXRα-LBD 和 的结合模式。
