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

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.

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