文章：

吗啉取代四氢喹啉衍生物作为潜在mTOR抑制剂：合成、计算解析与细胞分析

Morpholine-Substituted Tetrahydroquinoline Derivatives as Potential mTOR Inhibitors: Synthesis, Computational Insights, and Cellular Analysis

原文发布日期：23 February 2025

DOI: 10.3390/cancers17050759

类型: Article

开放获取: 是

英文摘要：

Backgrounds:This study explores the design of substituted tetrahydroquinoline (THQ) derivatives and their synthesis as possible inhibitors of mTOR inhibitors for targeted cancer therapy.Methods:Inspired by the structural characteristics of known mTOR inhibitors, eight novel derivatives were synthesized, characterized using mass spectroscopy,1H, and13C NMR, and evaluated for anticancer activity.Results:Computational studies, including molecular docking and molecular dynamics (MD) simulations, highlighted the derivative’s strong binding interaction and stability within the mTOR active site. Assays for in vitro cytotoxicity showed strong and specific anticancer action against cell lines of triple-negative breast cancer, lung cancer, and breast cancer while causing negligible impact on healthy cells.Conclusions:Compound10eemerged as the most promising candidate, displaying exceptional activity against A549 cells (IC50= 0.033 µM) and inducing apoptosis in a dose-dependent manner, surpassing standard agents, like Everolimus and 5-flurouracil. Structure–activity relationship analysis revealed that incorporating trifluoromethyl and morpholine moieties significantly enhanced selectivity and potency. MD simulations further validated these findings, confirming stable protein-ligand interactions and favorable dynamics over a 100-ns simulation period. Collectively, this study underscores the therapeutic potential of THQ derivatives, particularly compound10e, as promising mTOR inhibitors with potential applications in lung cancer treatment.

摘要翻译： 

背景：本研究旨在探索取代四氢喹啉衍生物的设计及其作为潜在mTOR抑制剂在靶向癌症治疗中的合成应用。 方法：基于已知mTOR抑制剂的结构特征，合成了八种新型衍生物，并通过质谱、核磁共振氢谱与碳谱进行结构表征，同时评估其抗癌活性。 结果：计算研究（包括分子对接和分子动力学模拟）显示该衍生物在mTOR活性位点具有强结合作用与稳定性。体外细胞毒性实验表明，该衍生物对三阴性乳腺癌、肺癌及乳腺癌细胞系表现出强效特异性抗癌作用，而对健康细胞影响甚微。 结论：化合物10e展现出最显著潜力，其对A549细胞的抑制活性（IC50=0.033 µM）优于依维莫司和5-氟尿嘧啶标准药物，并能以剂量依赖性方式诱导细胞凋亡。构效关系分析表明，三氟甲基和吗啉基团的引入显著增强了选择性与效力。分子动力学模拟进一步验证了这些发现，在100纳秒模拟周期内证实了稳定的蛋白-配体相互作用与良好的动力学特性。本研究共同揭示了四氢喹啉衍生物（尤其是化合物10e）作为新型mTOR抑制剂的治疗潜力，在肺癌治疗领域具有广阔应用前景。

原文链接：

Morpholine-Substituted Tetrahydroquinoline Derivatives as Potential mTOR Inhibitors: Synthesis, Computational Insights, and Cellular Analysis