1. Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids.
- Author
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Aoki S, Watanabe Y, Tanabe D, Arai M, Suna H, Miyamoto K, Tsujibo H, Tsujikawa K, Yamamoto H, and Kobayashi M
- Subjects
- Alkaloids chemistry, Alkaloids isolation & purification, Alkaloids pharmacology, Angiogenesis Inhibitors isolation & purification, Animals, Cell Movement drug effects, Cytostatic Agents isolation & purification, Endothelium, Vascular cytology, Endothelium, Vascular metabolism, Fibroblast Growth Factors pharmacology, Humans, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Phosphorylation drug effects, Steroids chemistry, Steroids isolation & purification, Steroids pharmacology, Structure-Activity Relationship, Umbilical Veins cytology, Umbilical Veins drug effects, Vascular Endothelial Growth Factor A pharmacology, Angiogenesis Inhibitors chemistry, Angiogenesis Inhibitors pharmacology, Cytostatic Agents chemistry, Cytostatic Agents pharmacology, Endothelium, Vascular drug effects, Porifera chemistry
- Abstract
Previously, bioassay-guided separation led us to isolate eleven novel steroidal alkaloids named cortistatins from the marine sponge Corticium simplex. These cortistatins were classified into three types based on the chemical structure of the side chain part, that is, isoquinoline, N-methyl piperidine or 3-methylpyridine units. From the structure-activity relationship study, the isoquinoline unit in the side chain was found to be crucial for the anti-angiogenic activity of cortistatins. Cortistatin A (1) showed cytostatic growth-inhibitory activity against human umbilical vein endothelial cells (HUVECs). Cortistatin A (1) also inhibited VEGF-induced migration of HUVECs and bFGF-induced tubular formation. Although cortistatin A (1) showed no effect on VEGF-induced phosphorylation of ERK1/2 and p38, which are one of the signaling pathways for migration and tubular formation, the phosphorylation of the unidentified 110kDa protein in HUVECs was inhibited by the treatment with cortistatin A.
- Published
- 2007
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