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  3. Discovery of marine ent-eudesmane sesquiterpenoids as angiogenic inhibitors via suppressing VEGF-A/VEGFR2 signaling pathway

Discovery of marine ent-eudesmane sesquiterpenoids as angiogenic inhibitors via suppressing VEGF-A/VEGFR2 signaling pathway

  • Bioorg Chem. 2025 Jan:154:108055. doi: 10.1016/j.bioorg.2024.108055.
Wan-Shan Li 1,  Xue-Ping Lei 2,  Zhan Li 2,  Yong He 3,  Mu Chen 2,  Zhong-Ping Jiang 4,  Guang-Ying Chen 5
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China. Electronic address: mimowanshan@163.com.
  • 2 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, College of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
  • 3 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China. Electronic address: zpjiang@hainanu.edu.cn.
  • 5 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China. Electronic address: chgying123@163.com.
PMID: 39700827 DOI: 10.1016/j.bioorg.2024.108055
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/KDR/Flk-1 signaling pathway. Our findings give insight into the application of marine ent-eudesmane sesquiterpenoids as potential angiogenesis inhibitor.

Keywords

Anti-angiogenic; Ent-eudesmane sesquiterpenoids; Marine-derived fungi; VEGF-A/VEGFR2 signaling pathway.

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