Total synthesis and target identification of marine cyclopiane diterpenes

IF 14.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Tian Li, Shan Jiang, Yuanhao Dai, Xia Wu, Huihui Guo, Liang Shi, Xueli Sang, Li Ren, Jie Wang, Lili Shi, Wenming Zhou, Houhua Li, Hong-Dong Hao
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Abstract

Marine cyclopianes are a family of diterpenoid with novel carbon skeleton and diverse biological activities. Herein, we report our synthetic and chemical proteomics studies of cyclopiane diterpenes which culminate in the asymmetric total synthesis of conidiogenones C, K and 12β-hydroxy conidiogenone C, and identification of Immunity-related GTPase family M protein 1 (IRGM1) as a cellular target. Our asymmetric synthesis commences from Wieland-Miescher ketone and features a sequential intramolecular Pauson-Khand reaction and gold-catalyzed Nazarov cyclization to rapidly construct the 6-5-5-5 tetracyclic skeleton. The stereocontrolled cyclopentenone construction is further investigated on complex settings to demonstrate its synthetic utility. Furthermore, using an alkyne-tagged conidiogenone C-derived probe, IRGM1, a master regulator of type I interferon responses, is identified as a key cellular target of conidiogenone C responsible for its anti-inflammatory activity. Preliminary mechanism of action studies shows that conidiogenone C activates IRGM1-mediate dysfunctional mitochondria autophagy to maintain mitochondria quality control of inflammatory macrophages.

Abstract Image

海洋环烷二萜的全合成及靶标鉴定
海洋环萜类化合物是一类碳骨架新颖、生物活性丰富的二萜类化合物。在此,我们报道了环蒎烯二萜的合成和化学蛋白质组学研究,最终不对称合成了分生子酮C、K和12β-羟基分生子酮C,并鉴定了免疫相关GTPase家族M蛋白1 (IRGM1)作为细胞靶点。我们的不对称合成从Wieland-Miescher酮开始,通过连续的分子内Pauson-Khand反应和金催化的Nazarov环化,快速构建6-5-5-5四环骨架。在复杂环境下进一步研究了立体控制环戊酮的结构,以证明其合成用途。此外,利用炔标记的内生内生因子C衍生探针,IRGM1, I型干扰素应答的主要调节因子,被确定为负责其抗炎活性的内生内生因子C的关键细胞靶点。初步作用机制研究表明,分生孢子素C激活irgm1介导的功能失调线粒体自噬,维持炎性巨噬细胞线粒体质量控制。
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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