五环三萜葡萄糖缀合物的设计、合成及体外抗流感病毒活性研究  

Design,Synthesis of Pentacyclic Triterpenoid Glucose Conjugate and in vitro Activity against Influenza Virus

作　　者：蔡铭 邵亮 杨帆 张继虹 俞飞 Cai Ming;Shao Liang;Yang Fan;Zhang Jihong;Yu Fei(Medical Faculty,Kunming University of Science and Technology,Kunming 650500;State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191)

机构地区：[1]昆明理工大学医学院,昆明650500 [2]北京大学药学院天然药物及仿生药物国家重点实验室,北京100191

出　　处：《有机化学》2022年第5期1453-1462,共10页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.22167018);天然药物及仿生药物国家重点实验室开放基金(No.K202003);云南省科技厅科技计划(Nos.2019FB125,2018FB145)资助项目。

摘　　要：前期研究发现齐墩果酸(OA)的C28位葡萄糖偶联物在细胞水平具有显著抗流感病毒的活性,但不同五环三萜母核偶联葡萄糖抗流感病毒活性的影响并未阐明.本研究采用不同五环三萜母核,通过Cu(I)催化的炔烃-叠氮化物环加成反应(CuAAC),与葡萄糖偶联制备得到化合物物4c~8d,通过体外抗流感病毒A/WSN/33(H1N1)活性研究,发现化合物4d具有显著的抗流感病毒活性(IC_(50)为9.09μmol/L),且对MDCK(Madin-Darbey Canine Kidney)细胞无明显毒性(CC_(50)>100μmol/L).构效关系研究明确了葡萄糖模块以及五环三萜母核对化合物抗流感病毒活性的提升均具有重要作用.本研究进一步完善了五环三萜及其衍生物抗流感病毒的构效关系,为这类天然产物抗病毒的深入研究奠定了基础.Previous studies have revealed that oleanolic acid(OA)C28-glucose conjugate displayed potent anti-influenza viral activity in vitro.However,the effect of pentacyclic triterpene scaffold coupled with glucose on anti-influenza virus activity has not been clarified.Herein,as a continuous further study,a series of pentacyclic triterpene-glucose conjugates were prepared via CuAAC reaction,and the anti-influenza activity of these compounds was evaluated in vitro.Among them,compound 4d,an betulinic acid(BA)-glucose conjugate,showed potent anti-influenza virus activity(IC_(50) value of 9.09μmol/L),and no obvious cytotoxic effect on MDCK(Madin-Darbey Canine Kidney)cells was observed(CC_(50)>100μmol/L).Structure-activity relationship studies showed that both triterpene scaffolds and glucose moiety have important effects on the anti-viral activity.Overall,this finding further extends the utility of triterpene derivatives in anti-influenza virus drug design.

关 键 词：五环三萜 流感病毒 进入抑制剂 构效关系 

分 类 号：TQ460.1[化学工程—制药化工]