奇壬醇的结构修饰及其抗凝血因子FXa活性研究  

Study on structure modification of kirenol and activity of its anticoagulant factor FXa

作　　者：陈安琪 陈锡庆 陈丽[1] 庞汉青 刘量[1,2] 王建斌 CHEN An-qi;CHEN Xi-qing;CHEN Li;PANG Han-qing;LIU Liang;WANG Jian-bin(Institute of Translational Medicine,School of Medicine,Yangzhou University,Yangzhou 225009,China;Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases,Yangzhou University,Yangzhou 225009,China)

机构地区：[1]扬州大学医学院(转化医学院),江苏扬州225009 [2]江苏省中西医结合老年病防治重点实验室,江苏扬州225009

出　　处：《中草药》2023年第17期5498-5507,共10页Chinese Traditional and Herbal Drugs

基　　金：国家自然科学基金资助项目(81903481);中国博士后科学基金(2019M653297);扬州市“绿扬金凤计划”(YZLYJFJH2021YXB);扬州大学大学生学术科技创新基金(X20220736)。

摘　　要：目的研究有抗凝血因子FXa活性的奇壬醇衍生物,发现具有开发价值的先导化合物。方法通过氧化、酯化、酰胺化反应,对奇壬醇进行结构修饰,采用核磁和质谱数据对这些衍生物进行表征,并通过以FXa为靶标的计算机辅助药物设计结合体外抗凝血因子FXa试验评价衍生物的活性;结果得到奇壬醇衍生物15个,其中新化合物14个(化合物2~15),体外抗凝血因子FXa活性筛选得到1个活性较好的衍生物(化合物12),抑制常数(inhibitor constant,Ki值)为(589.40±80.12)nmol/L。结论计算机辅助药物设计和体外凝血因子FXa试验结果显示化合物12的抑制活性最好,为继续开展奇壬醇的结构修饰研究提供有益参考,具有一定的研究价值。Objective To study kirenol derivatives with anticoagulant factor FXa activity and identify lead compounds with developmental value..Methods The structural modification of kirenol was conducted through oxidation,esterification and amidation reaction.The structures of them were fully determined on the basis of NMR and MS data.The activity evaluation of kirenol and its derivatives was revealed by the virtual screening of computer-aided drug design(CADD)using FXa as target,combined with the evaluation of the inhibition on FXa in vitro.Results A total of 15 kirenol derivatives including 14 new compounds(compounds 2-15)were obtained,and the activity evaluation of them on FXa yielded an active compound(compound 12)with Ki value of(589.4±80.12)nmol/L.Conclusion The results of CADD and in vitro coagulation factor FXa assay showed the best inhibitory activity of compound 12,which is a useful reference for the continuation of the structural modification study of kirenol,and has some research value.

关 键 词：奇壬醇 先导化合物 结构修饰 凝血因子FXa 计算机辅助药物设计 

分 类 号：R284[医药卫生—中药学]