齐墩果酸C3-糖缀合物的设计、合成及抗流感病毒活性研究  

Design,Synthesis and Anti-influenza A Virus Evaluation of Oleanolic Acid C3-Glycoconjugates

作　　者：邵亮 杨帆 李唯嘉 俞飞 Shao Liang;Yang Fan;Li Weijia;Yu Fei(School of Medical,Kunming University of Science and Technology,Kunming 650500;State Key Laboratory of Natural and Biomimetic Drugs,Peking University,Beijing 100191)

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

出　　处：《有机化学》2021年第6期2454-2466,共13页Chinese Journal of Organic Chemistry

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

摘　　要：靶向流感病毒进入阶段的抑制剂是抗流感药物研发的热点.前期研究发现,齐墩果酸(OA)的C28位糖基化衍生物具有较强的抗流感病毒活性.本研究采用Cu(I)催化叠氮-炔基Husigen环加成(Cu AAC)反应设计合成了一系列齐墩果酸(C3)-糖缀合物7a~14c.体外抗病毒研究发现,齐墩果烷-12-烯-28-苄氧羰基-3-O-(4-亚甲基-1,2,3-三唑-1-(2,3,4,6-四-O-乙酰基-β-D-半乳糖苷))(12a)具有显著的抗流感病毒活性,IC50为12.45μmol·L^(-1),且无明显的细胞毒性(CC50>100μmol·L^(-1)).血凝抑制和分子对接实验表明,化合物12a可能靶向流感病毒的膜蛋白血凝素(HA),通过阻断HA与宿主细胞表面的唾液酸受体结合,达到抑制流感病毒感染的目的.本研究进一步完善了齐墩果酸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提供依据.Inhibitors targeting the entry stage of influenza viruses are a hot spot in the development of anti-influenza drugs.Our previous studies showed that oleanolic acid(OA)C28 glycoconjugates displayed strong anti-influenza virus activity.In this paper,a series of oleanolic acid C3 glycoconjugates 7a~14c were designed and synthesized via copper(I)-catalyzed alkyne-azide cycloaddition(CuAAC)reaction.The anti-influenza activities of all these compounds were evaluated in vitro.Among them,oleanane-12-enyl-28-benzyloxycarbonyl-3-O-(4-methylene-1,2,3-triazole-1-(2,3,4,6-tetra-O-acetyl-β-D-galactoside))(12a)showed the strongest activity with an IC50 of 12.45μmol·L^(-1),and no obvious cytotoxic effect on MDCK cells was observed at 100μmol·L^(-1).Hemagglutination inhibition and molecular docking experiments indicated that compound 12a might target viral envelope hemagglutinin(HA),thus inhibiting the attachment of viruses to host cells.This study improved the structure-activity relationships of oleanolic acid and its derivatives against influenza virus,and provided a basis for further research on anti-virus by these natural products.

关 键 词：齐墩果酸 糖缀合物 流感病毒 CuAAC反应 抑制剂 

分 类 号：TQ460.1[化学工程—制药化工]