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

doi:10.6023/cjoc202010029

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (6): 2454-2466.DOI: 10.6023/cjoc202010029 Previous Articles Next Articles

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齐墩果酸C3-糖缀合物的设计、合成及抗流感病毒活性研究

邵亮^a, 杨帆^a, 李唯嘉^a, 俞飞^a^,^b^,^*()

a 昆明理工大学医学院昆明 650500
b 北京大学天然药物与仿生药物国家重点实验室北京 100191

收稿日期:2020-10-21 修回日期:2020-12-15 发布日期:2021-02-22
通讯作者: 俞飞
作者简介:
† 共同第一作者
基金资助:
云南省科技厅科技计划(2019FB125); 天然药物及仿生药物国家重点实验室开放基金(K202003)

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

Liang Shao^a, Fan Yang^a, Weijia Li^a, Fei Yu^a^,^b()

a School of Medical, Kunming University of Science and Technology, Kunming 650500
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191

Received:2020-10-21 Revised:2020-12-15 Published:2021-02-22
Contact: Fei Yu
About author:
(These authors contributed equally to this work).
Supported by:
Science and Technology Plan Project of Yunnan Provincial Department of Science and Technology(2019FB125); Open-Fund Program of the State Key Laboratory of Natural and Biomimetic Drugs(K202003)

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Abstract

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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Liang Shao, Fan Yang, Weijia Li, Fei Yu. Design, Synthesis and Anti-influenza A Virus Evaluation of Oleanolic Acid C3-Glycoconjugates[J]. Chinese Journal of Organic Chemistry, 2021, 41(6): 2454-2466.

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Fig. & Tab. 5

Figure 1. Structural formula of OA(28)-glucose conjugate

Scheme 1. Synthetic routes of compounds 7a~14c Reagents and conditions: (a) Ac2O, DMAP, pyridine, r.t., overnight; (b) HBr, CH2Cl2, 0 ℃ to r.t., overnight; (c) NaN3, DMF, r.t., overnight; (d) benzyl bromide, Na2CO3, DMF, 50 ℃ 6 h; (e) propargyl bromide, NaH, dry THF, r.t., 6 h; (f) CuSO4•5H2O, Na-L-ascorbate, CH2Cl2/H2O, r.t., overnight; (g) MeONa, MeOH, r.t.,3 h; (h) Pd/C, H2,THF, 48 h.

Figure 2. Inhibitory activity of compounds 7a~14c anti-influenza virus in vitro (A) The cytotoxic effect-based screen of OA-saccharide conjugates 7a~14c (100 µmol•L –1); (B) Inhibitory activity of Compounds 7a~14c (100 µmol• L –1) anti-A/WSN/33. Oseltamivir phosphate (OSV-p) was used as the positive control, DMSO was used as the negative control, and Error bars indicate standard deviations of triplicate experiments.

Figure 3. (A) Compound 12a effectively inhibited CPE induced by A/WSN/33, and (B) comparisons of 12a and anti-HA antibody for inhibiting influenza virus induced aggregation of chicken erythrocytes

Figure 4. Docking of compound 12a and HA protein molecule simulates (A) the binding site of compound 12a in HA protein, (B) the 3D model diagram of the interaction between compound 12a and HA protein, and (C) the 2D model diagram of the interaction between compound 12a and HA protein

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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

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