Chemical modification of fumagillin. I. 6-O-acyl, 6-O-sulfonyl, 6-O-alkyl, and 6-O-(N-substituted-carbamoyl)fumagillols.
The hydroxy group of fumagillol (3), a degradation product of fumagillin (1), was acylated, sulfonylated, alkylated or carbamoylated, and the anti-angiogenic activity of the resulting products was examined. These compounds inhibited the angiogenesis induced by basic fibroblast growth factor in the rat corneal micropocket assay and the growth of vascular endothelial cells in vitro. Among them, compound 2 (AGM-1470) was found to show the most potent inhibitory effect on the growth of vascular endothelial cells and was selected from this series as a candidate for further development.
Marui
S
S
Chemistry Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Itoh
F
F
Kozai
Y
Y
Sudo
K
K
Kishimoto
S
S
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003510:Cyclohexanes; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000494:pharmacology
D003510:Cyclohexanes; D012717:Sesquiterpenes; D016222:Fibroblast Growth Factor 2; C057299:fumagillol