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Two new meroterpenoids, hyrtamide A (<b>1</b>) and hyrfarnediol A (<b>2</b>), along with two known ones, 3-farnesyl-4-hydroxybenzoic acid methyl ester (<b>3</b>) and dictyoceratin C (<b>4</b>), were isolated from a South China Sea sponge <i>Hyrtios</i> sp. Their structures were elucidated by NMR and MS data. Compounds <b>2</b>–<b>4</b> exhibited weak cytotoxicity against human colorectal cancer cells (HCT-116), showing IC₅₀ values of 41.6, 45.0, and 37.3 μM, respectively. Furthermore, compounds <b>3</b> and <b>4</b> significantly suppressed the invasion of HCT-116 cells while also downregulating the expression of vascular endothelial growth factor receptor 1 (VEGFR-1) and vimentin proteins, which are key markers associated with angiogenesis and epithelial–mesenchymal transition (EMT). Our findings suggest that compounds <b>3</b> and <b>4</b> may exert their anti-invasive effects on tumor cells by inhibiting the expression of VEGFR-1 and impeding the process of EMT.