Pyripyropenes, Fungal Sesquiterpenes Conjugated with alpha-Pyrone and Pyridine Moieties, Exhibits Anti-angiogenic Activity against Human Umbilical Vein Endothelial Cells

摘要

In the course of our search for anti-angiogenic substances, pyripyropenes A (1), B (2), and D (3) were rediscovered as selective anti-proliferative substances against human umbilical vein endothelial cells (HUVECs) from a marine-derived fungus of Aspergillus sp. Pyripyropenes showed potent anti-proliferative activity against HUVECs with IC50 values of the range of 0.1-1.8 mu M, which were cytostatic at 0.05 to 20 mu M. The selective index was more than 55-fold in comparison with those of several tumor cell lines. Compound I inhibited vascular endothelial growth factor (VEGF)-induced migration and tubular formation of HUVECs, while I showed no effect on the VEGF-induced phosphorylations of extracellular signal-regulated kinase (ERK)1/2, p38, and Akt. Pyripyropenes were originally isolated as an inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT-2). While, the expression level of ACATs between HUVECs and other tumor cell lines did not correspond to the selective index of the anti-proliferative activity of compound 1. Moreover, ACATs inhibitor, 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976), showed growth inhibitory activity with only poor selectivity (2.4-fold) between HUVECs and human epidermoid carcinoma KB3-1 cells.