POSSIBLE FUNCTIONAL GROUPS RESPONSIBLE FOR INHIBITION OF IN VIVO ANGIOGENESIS BY HERBIMYCIN A

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Six herbimycin A (HBM) derivatives were examined for their anti-angiogenic effects in a bioassay system involving chorioallantoic membranes (CAMs) of growing chick embryos on the basis of our previous observation that HBM is a potent angiogenesis inhibitor. 17-Cyclopropylamino-HBM dose-dependently inhibited embryonic angiogenesis. The ID₅₀ value was 0.1 μg (160 pmol) per egg and thereby lower than that of the parent compound HBM (ID₅₀=0.15 μg (260 pmol) per egg). In contrast, 19-dimethylamino-, N-acetyl-, 2, 3, 4, 5-tetrahydro- and 7-decarbamoyl-HBM at doses of 0.01-10 μg/egg failed to affect angiogenesis in CAMs. These results strongly suggest as follows : (1) C-19 position, amino group between positions C-1 and C-20 and carbamoyl group in C-7 are essential for the anti-angiogenic action of HBM ; (2) HBM needs certain fixed conformation for expression of angiogenesis inhibition ; (3) it is expected that the modification of C-17 with a suitable functional group results in increased anti-angiogenic potency of HBM - - that is, a more potent angiogenesis inhibitor than the parent compound would be developed.