{"title":"Discovery of marine ent-eudesmane sesquiterpenoids as angiogenic inhibitors via suppressing VEGF-A/VEGFR2 signaling pathway.","authors":"Wan-Shan Li, Xue-Ping Lei, Zhan Li, Yong He, Mu Chen, Zhong-Ping Jiang, Guang-Ying Chen","doi":"10.1016/j.bioorg.2024.108055","DOIUrl":null,"url":null,"abstract":"<p><p>Increasing evidence underscores the pivotal role of tumor angiogenesis for tumorigenesis and tumor metastasis. Inhibiting the tumor angiogenesis process is a promising therapeutic approach for cancer. In order to search for natural angiogenic inhibitors, the chemical constitutes of a marine-derived fungus Eutypella sp. F0219 were investigated, leading to the isolation and identification of twelve new ent-eudesmane sesquiterpenoids named eutypenes A-L (1-12). Their structures including absolute configurations were determined by extensive spectroscopic investigations, single crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Notably, eutypene A (1) represents a rare rearranged ent-eudesmane sesquiterpenoid with 5/7 fused ring system. Tube formation assay was performed to evaluate the antiangiogenic effect of all compounds. The results showed that compounds 4, 6, 7, 9, and 10 obviously suppressed the tube formation of human microvascular endothelial cell line (HMEC-1) cells in a dose-dependent manner. Moreover, the most bioactive and less toxic compound 9 displayed significant antiangiogenic effect in vitro and ex vivo. Further mechanistic investigation revealed that compound 9 restrained tumor angiogenesis by reducing the VEGF-A level and suppressing the VEGF-A/VEGFR2 signaling pathway. Our findings give insight into the application of marine ent-eudesmane sesquiterpenoids as potential angiogenesis inhibitor.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108055"},"PeriodicalIF":4.5000,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1016/j.bioorg.2024.108055","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Increasing evidence underscores the pivotal role of tumor angiogenesis for tumorigenesis and tumor metastasis. Inhibiting the tumor angiogenesis process is a promising therapeutic approach for cancer. In order to search for natural angiogenic inhibitors, the chemical constitutes of a marine-derived fungus Eutypella sp. F0219 were investigated, leading to the isolation and identification of twelve new ent-eudesmane sesquiterpenoids named eutypenes A-L (1-12). Their structures including absolute configurations were determined by extensive spectroscopic investigations, single crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Notably, eutypene A (1) represents a rare rearranged ent-eudesmane sesquiterpenoid with 5/7 fused ring system. Tube formation assay was performed to evaluate the antiangiogenic effect of all compounds. The results showed that compounds 4, 6, 7, 9, and 10 obviously suppressed the tube formation of human microvascular endothelial cell line (HMEC-1) cells in a dose-dependent manner. Moreover, the most bioactive and less toxic compound 9 displayed significant antiangiogenic effect in vitro and ex vivo. Further mechanistic investigation revealed that compound 9 restrained tumor angiogenesis by reducing the VEGF-A level and suppressing the VEGF-A/VEGFR2 signaling pathway. Our findings give insight into the application of marine ent-eudesmane sesquiterpenoids as potential angiogenesis inhibitor.
期刊介绍:
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.