Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
Chemistry Department, College of Sciences, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.
Bioorg Chem. 2021 Jun;111:104835. doi: 10.1016/j.bioorg.2021.104835. Epub 2021 Mar 22.
This study reports an efficient and convenient click chemistry synthesis of a novel series of phthalimide scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of newly synthesized compounds were well characterized by different spectroscopic tools. In vitro MTT cytotoxicity assay was performed comparing the cytotoxic effects of newly synthesized compounds to staurosporine using three different types: human liver cancer cell line (HepG2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). The initial screening showed excellent to moderate anticancer activity for these newly synthesized compounds with high degree of cell line selectivity with micromolar (µM) half maximal inhibitory concentration (IC) values against tumor cells. The SAR analysis of these derivatives confirmed the role of molecular fragments including phthalimide, linker, triazole, and terminal tails in correlation to activity. In addition, enzymatic inhibitory assay against wild type EGFR was performed for the most active compounds to get more details about their mechanism of action. In order to further explore their binding affinities, molecular docking simulation was studied against EGFR site. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. One of the most prominent analogs is (6f) with terminal disubstituted ring and amide linker showed selective MCF-7 cytotoxicity profile with IC 0.22 µM and 79 nM to EGFR target. Extensive structure activity relationship (SAR) analyses were also carried out. The pharmacokinetic profile of (6f) was studied showing good metabolic stability and long duration behavior. This design offered a potent selective anticancer phthalimide-triazole leads for further optimization in cancer drug discovery.
本研究报告了一种新型系列邻苯二甲酰亚胺支架与 1,2,3-三唑环和末端亲脂性片段连接的高效、便捷点击化学合成方法。新合成化合物的结构通过不同的光谱工具得到了很好的表征。采用三种不同类型（人肝癌细胞系 HepG2、密歇根癌症基金会-7 MCF-7 和人结肠直肠癌细胞系 HCT116）进行体外 MTT 细胞毒性测定，比较了新合成化合物与星形孢菌素的细胞毒性作用。初步筛选结果表明，这些新合成化合物具有优异至中等的抗癌活性，对肿瘤细胞的半最大抑制浓度（IC）值为微摩尔（µM）级，具有高度的细胞系选择性。这些衍生物的 SAR 分析证实了分子片段，包括邻苯二甲酰亚胺、连接物、三唑和末端尾部，与活性相关的作用。此外，还针对野生型 EGFR 进行了酶抑制测定，以获得更多关于其作用机制的信息。为了进一步探讨它们的结合亲和力，对 EGFR 位点进行了分子对接模拟研究。从分子对接研究中获得的结果与从细胞毒性筛选中获得的结果相关联。其中最突出的类似物是（6f），其末端取代的环和酰胺连接基对 MCF-7 具有选择性细胞毒性，IC 0.22µM 和 79nM 对 EGFR 靶点。还进行了广泛的构效关系（SAR）分析。研究了（6f）的药代动力学特征，表明其具有良好的代谢稳定性和较长的作用时间。该设计提供了一种有效的选择性抗癌邻苯二甲酰亚胺-三唑先导化合物，可进一步优化用于癌症药物发现。
