基于药效团的半合成方法从天然产物中发现抗 SARS-CoV-2 先导化合物的研究进展。
Harnessing Natural Products by a Pharmacophore-Oriented Semisynthesis Approach for the Discovery of Potential Anti-SARS-CoV-2 Agents.
机构信息
State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming, 650201, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
出版信息
Angew Chem Int Ed Engl. 2022 Jul 11;61(28):e202201684. doi: 10.1002/anie.202201684. Epub 2022 May 12.
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 EC value (19±1 nM) and a high TI value (>1000), both values better than those of remdesivir.
天然产物具有独特的结构骨架，可能具有抗病毒活性，但它们的复杂结构阻碍了其轻易合成。本研究采用基于药效团的半合成方法，对（-）-绵马酸内酯 A（1）和冬凌草甲素（2）进行结构修饰，以期发现抗 SARS-CoV-2 药物。该研究开发了 Wolff 重排/内酯化级联（WRLC）反应，用于 1 的半合成过程中构建前所未有的绵马酸内酯型骨架。进一步的机制研究表明，Wolff 重排是协同反应，内酯化则是经水辅助的分步过程。随后，WRLC 反应通过组装绵马酸内酯型骨架和 2 的药效团，创建了一个新的化合物家族，其中一个衍生物对 HPA EpiC 细胞中的 SARS-CoV-2 复制具有低 EC 值（19±1 nM）和高 TI 值（>1000）的抑制活性，优于瑞德西韦。
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