Pyripyropenes, fungal sesquiterpenes conjugated with alpha-pyrone and pyridine moieties, exhibits anti-angiogenic activity against human umbilical vein endothelial cells.

Abstract

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.

• Authors: Asami Hayashi, Masayoshi Arai, Mayumi Fujita, Motomasa Kobayashi
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 32 Issue 7 Pg. 1261-5 (Jul 2009) ISSN: 0918-6158 [Print] Japan
• PMID: 19571395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Pyridines
• Pyrones
• Recombinant Proteins
• Sesquiterpenes
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• pyripyropene A
• pyripyropene B
• pyripyropene D
• Sterol O-Acyltransferase
• sterol O-acyltransferase 1
• sterol O-acyltransferase 2

Topics

• Angiogenesis Inhibitors (chemistry, isolation & purification, pharmacology)
• Aspergillus (chemistry)
• Cell Line
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Neovascularization, Pathologic (prevention & control)
• Pyridines (chemistry, isolation & purification, pharmacology)
• Pyrones (chemistry)
• Recombinant Proteins (pharmacology)
• Sesquiterpenes (chemistry, isolation & purification, pharmacology)
• Sterol O-Acyltransferase (biosynthesis)
• Vascular Endothelial Growth Factor A (pharmacology)