Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids.
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.
Aoki
Shunji
S
Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-Oka 1-6, Suita, Osaka, Japan.
Watanabe
Yasuo
Y
Tanabe
Daiki
D
Arai
Masayoshi
M
Suna
Hideaki
H
Miyamoto
Katsushiro
K
Tsujibo
Hiroshi
H
Tsujikawa
Kazutake
K
Yamamoto
Hiroshi
H
Kobayashi
Motomasa
M
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D054697:Cytostatic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D013256:Steroids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D054697:Cytostatic Agents; D013256:Steroids; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3