Pyripyropenes, fungal sesquiterpenes conjugated with alpha-pyrone and pyridine moieties, exhibits anti-angiogenic activity against human umbilical vein endothelial cells.
In the course of our search for anti-angiogenic substances, pyripyropenes A (1), B (2), and D (3) were re-discovered 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 IC(50) values of the range of 0.1-1.8 muM, which were cytostatic at 0.05 to 20 muM. The selective index was more than 55-fold in comparison with those of several tumor cell lines. Compound 1 inhibited vascular endothelial growth factor (VEGF)-induced migration and tubular formation of HUVECs, while 1 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.
Hayashi
Asami
A
Graduate School of Pharmaceutical Sciences, Osaka University.
Arai
Masayoshi
M
Fujita
Mayumi
M
Kobayashi
Motomasa
M
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001230:Aspergillus / Q000737:chemistry*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011725:Pyridines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011753:Pyrones / Q000737:chemistry*; D011994:Recombinant Proteins / Q000494:pharmacology; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000097587:Sterol O-Acyltransferase 2
D020533:Angiogenesis Inhibitors; D011725:Pyridines; D011753:Pyrones; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D002785:Sterol O-Acyltransferase; D042461:Vascular Endothelial Growth Factor A; D000097587:Sterol O-Acyltransferase 2; C467484:VEGFA protein, human; C082792:pyripyropene A; C082793:pyripyropene B; C082795:pyripyropene D; C493492:sterol O-acyltransferase 1