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

Six herbimycin A (HBM) derivatives were examined for their anti-angiog enic effects in a bioassay system involving chorioallantoic membranes (CAMs) of growing chick embryos on the basis of our previous observati on that HBM is a potent angiogenesis inhibitor. 17-Cyclopropylamino-HB M dose-dependently inhibited embryonic angiogenesis. The ID50 value wa s 0.1 mu g (160 pmol) per egg and thereby lower than that of the paren t compound HBM (ID50=0.15 mu g (260 pmol) per egg). In contrast, 19-di methylamino-, N-acetyl-, 2,3,4,5-tetrahydro- and 7-decarbamoyl-HBM at doses of 0.01-10 mu g/egg failed to affect angiogenesis in CAMs. These results strongly suggest as follows: (1) C-19 position, amino group b etween 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 co nformation for expression of angiogenesis inhibition; (3) it is expect ed that the modification of C-17 with a suitable functional group resu lts in increased anti-angiogenic potency of HBM - - that is, a more po tent angiogenesis inhibitor than the parent compound would be develope d.