吴茱萸次碱衍生物血管舒张活性评价及分子对接模拟研究  

Evaluation of Vasodilatory Activity and Molecular Docking Simulation of Wuzhuyu Alkaloid Derivatives

作　　者：周耀彬 高冬梅[3] 王一峰 王婷 高宇飞 张玫倩 王川 周静 ZHOU Yaobin;GAO Dongmei;WANG Yifeng;WANG Ting;GAO Yufei;ZHANG Meiqian;WANG Chuan;ZHOU Jing(School of Pharmacy,Shaanxi University of Chinese Medicine,Shaanxi Xianyang 712046,China;School of Medical Technology,Shaanxi University of Chinese Medicine,Shaanxi Xianyang 712046,China;Department of Pharmacy and Chemical Engineering,Yangling Vocational and Technical College,Shaanxi Yangling 712100,China;School of Basic Medicine,Shaanxi University of Chinese Medicine,Shaanxi Xianyang 712046,China)

机构地区：[1]陕西中医药大学药学院,陕西咸阳712046 [2]陕西中医药大学医学技术学院,陕西咸阳712046 [3]杨凌职业技术学院药物与化工系,陕西咸阳712100 [4]陕西中医药大学基础医学院,陕西咸阳712046

出　　处：《陕西中医药大学学报》2024年第5期91-96,共6页Journal of Shaanxi University of Chinese Medicine

基　　金：国家自然科学基金项目(22201169);陕西省科技厅青年基金项目(2021JQ-723);陕西省教育厅专项基金项目(21JK0601);国家级大创项目(202110716025)。

摘　　要：目的探讨新型吴茱萸次碱衍生物的细胞毒性、血管舒张活性及其作用机制。方法合成了6个吴茱萸次碱衍生物,并通过血管环试验对其血管舒张功能进行了测试,通过CCK-8细胞增殖实验和血管内皮细胞毒性实验对化合物的细胞毒性进行了评价。选取活性高的化合物,采用AutoDock软件进行分子对接,分析与eNOS酶的相互作用模式。结果共合成得到6个吴茱萸次碱衍生物,对其血管舒张功能结果显示吴茱萸次碱衍生物均对苯肾上腺素预收缩的大鼠肠系膜动脉具有舒张作用,其中吴茱萸次碱衍生物4c的舒张作用最强。细胞毒性评价显示,吴茱萸次碱衍生物中化合物4b、4e、4f对肝癌细胞的抑制率略低,细胞毒性比原药略微有所下降;化合物4a与原药的细胞毒性相当,化合物4c、4d细胞毒性略高于原药。内皮细胞存活率测定结果显示,化合物4c对内皮细胞的毒性与原药相当。分子对接结果显示,活性较高的化合物与eNOS酶具有很好的能量匹配,并且与该蛋白的活性氨基酸残基形成氢键,配体与受体具有良好的结合能力。结论分子对接结果与活性测定实验结果一致。这类吴茱萸次碱衍生物很可能通过激活eNOS酶的活性而具有了良好的血管舒张能力。Objective To investigate the cytotoxicity,vasodilatory activity,and mechanism of action of a novel derivative of rutaecarpa alkaloids.Methods Six derivatives of rutaecarpa alkaloids were synthesized and their vasodilation function was tested by vascular ring assay.The cytotoxicity of the compounds was evaluated by CCK-8 cell proliferation assay and endothelial cell toxicity assay.Select compounds with high activity,use AutoDock software for molecular docking,and analyze the interaction mode with eNOS enzyme.Results Six derivatives of rutaecarpa alkaloids were synthesized,and their vasodilation function was evaluated.The results showed that all derivatives of rutaecarpa alkaloids had a vasodilatory effect on the mesenteric arteries of rats pre contracted with phenylephrine,with derivative 4c of rutaecarpa alkaloids having the strongest vasodilatory effect.The cytotoxicity evaluation showed that compounds 4b,4e,and 4f in the derivatives of Evodia rutaecarpa alkaloids had slightly lower inhibition rates on liver cancer cells,and the cytotoxicity was slightly reduced compared to the original drug;The cytotoxicity of compound 4a is comparable to that of the original drug,while the cytotoxicity of compounds 4c and 4d is slightly higher than that of the original drug.The results of endothelial cell survival assay showed that compound 4c had similar toxicity to the original drug on endothelial cells.The molecular docking results showed that compounds with higher activity have good energy matching with eNOS enzyme,and form hydrogen bonds with the active amino acid residues of the protein.The ligand has good binding ability with the receptor.Conclusion The molecular docking results are consistent with the experimental results of activity determination.These derivatives of rutaecarpa alkaloids are likely to have good vasodilation ability by activating the activity of eNOS enzyme.

关 键 词：吴茱萸次碱衍生物 细胞毒性 血管舒张活性 分子对接 

分 类 号：R285[医药卫生—中药学]