摘要/Abstract

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(CuAAC)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12.45 µmol•L ^–1, 且无明显的细胞毒性(CC₅₀>100 µmol•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.
关键词: 齐墩果酸, 糖缀合物, 流感病毒, CuAAC反应, 抑制剂
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 evaluatedin 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 12.45 µmol•L ^–1, and no obvious cytotoxic effect on MDCK cells was observed at 100 µmol•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.
Key words: oleanolic acid, glycoconjugates, influenza virus, CuAAC reaction, inhibitors


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