Harnessing Natural Products by a Pharmacophore-Oriented Semisynthesis Approach for the Discovery of Potential Anti-SARS-CoV-2 Agents

被引：10

作者：

Zhou, Yuan-Fei ^{[1
,2
]}

Yan, Bing-Chao ^{[1
,2
]}

Yang, Qian ^{[1
,2
]}

Long, Xin-Yan ^{[3
]}

Zhang, Dan-Qi ^{[4
,5
]}

Luo, Rong-Hua ^{[3
]}

Wang, Han-Yu ^{[1
,2
]}

Sun, Han-Dong ^{[1
,2
]}

Xue, Xiao-Song ^{[4
,5
]}

Zheng, Yong-Tang ^{[3
]}

Puno, Pema-Tenzin ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Univ Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China

[2] Chinese Acad Sci, Univ Chinese Acad Sci, Kunming Inst Bot, Yunnan Key Lab Nat Med Chem, Kunming 650201, Yunnan, Peoples R China

[3] Chinese Acad Sci, Key Lab Anim Models & Human Dis Mech, Kunming Inst Zool, Kunming 650223, Yunnan, Peoples R China

[4] Nankai Univ, Coll Chem, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China

[5] Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Organ Chem, Key Lab Organofluorine Chem, 345 Lingling Rd, Shanghai 200032, Peoples R China

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2022年 / 61卷 / 28期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

Anti-SARS-CoV-2; Agents; Domino Reactions; Natural Products; Semisynthesis; Wolff Rearrangement; ORIDONIN; STRATEGY; ANALOGS;

D O I：

10.1002/anie.202201684

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Natural products possessing unique scaffolds may have antiviral activity but their complex structures hinder facile synthesis. A pharmacophore-oriented semisynthesis approach was applied to (-)-maoelactone A (1) and oridonin (2) for the discovery of anti-SARS-CoV-2 agents. The Wolff rearrangement/lactonization cascade (WRLC) reaction was developed to construct the unprecedented maoelactone-type scaffold during semisynthesis of 1. Further mechanistic study suggested a concerted mechanism for Wolff rearrangement and a water-assisted stepwise process for lactonization. The WRLC reaction then enabled the creation of a novel family by assembly of the maoelactone-type scaffold and the pharmacophore of 2, whereby one derivative inhibited SARS-CoV-2 replication in HPA EpiC cells with a low EC50 value (19 +/- 1 nM) and a high TI value (>1000), both values better than those of remdesivir.

引用

页数：9

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