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地珠菌素 H 的全合成及生物活性研究

Total Synthesis and Bioactivity Mapping of Geodiamolide H.

机构信息

Institut für Organische Chemie und Makromolekulare Chemie, Friedrich-Schiller-Universität (FSU), Humboldtstr. 10, 07743, Jena, Germany.

Abteilungen Infektionsbiologie und Paläobiotechnologie, Leibniz-Institut für Naturstoffforschung - Hans-Knöll-Institut, Beutenbergstr. 11a, 07745, Jena, Germany.

出版信息

Chemistry. 2021 Aug 11;27(45):11633-11642. doi: 10.1002/chem.202100989. Epub 2021 Jun 25.

DOI:10.1002/chem.202100989
PMID:34032329
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8453818/
Abstract

The first total synthesis of the actin-stabilizing marine natural product geodiamolide H was achieved. Solid-phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring-closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F-actin target and property computation in silico, for a better understanding of structure-activity relationships (SAR). A non-natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design.

摘要

成功实现了具有稳定肌动蛋白作用的海洋天然产物 geodiamolide H 的首次全合成。基于固相的肽偶联与可扩展的立体选择性聚酮砌块合成以及优化的酯化反应为研究关键的环 closing metathesis 奠定了基础。通过体外表征肌动蛋白聚合诱导作用、细胞内抗增殖作用以及在 F-actin 靶标上的对接和计算特性，研究了 geodiamolide H 和合成类似物的毒性，以更好地了解结构-活性关系 (SAR)。发现 geodiamolide H 的一种非天然类似物在该系列中最有效，这表明其在工具化合物设计方面具有很大的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/e315d7395072/CHEM-27-11633-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/3499cb753c3d/CHEM-27-11633-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/e0596c59f66d/CHEM-27-11633-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/3a78a2367de8/CHEM-27-11633-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/efbf27677e66/CHEM-27-11633-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/3867911aef5b/CHEM-27-11633-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/5cef17abffa7/CHEM-27-11633-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/e315d7395072/CHEM-27-11633-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/3499cb753c3d/CHEM-27-11633-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/e0596c59f66d/CHEM-27-11633-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/3a78a2367de8/CHEM-27-11633-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/efbf27677e66/CHEM-27-11633-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/3867911aef5b/CHEM-27-11633-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/5cef17abffa7/CHEM-27-11633-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f124/8453818/e315d7395072/CHEM-27-11633-g002.jpg

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