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

• Published in: Biological & pharmaceutical bulletin Vol. 17; no. 10; pp. 1430 - 1432
• Main Authors: OIKAWA, Tsutomu, OGASAWARA, Hiroyuki, SANO, Hiroshi, SHIBATA, Kiyoshi, OMURA, Satoshi
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.10.1994; Maruzen; Japan Science and Technology Agency
• Subjects: Allantois - blood supply; Allantois - drug effects; Animals; anti-angiogenic activity; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Benzoquinones; Biological and medical sciences; Cardiovascular system; Chick Embryo; Chorion - blood supply; Chorion - drug effects; Dose-Response Relationship, Drug; embryonic angiogenesis; herbimycin A derivative; Lactams, Macrocyclic; Lethal Dose 50; Medical sciences; Miscellaneous; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Quinones - chemistry; Quinones - pharmacology; Quinones - therapeutic use; Rifabutin - analogs & derivatives; Structure-Activity Relationship; Angiogenesis; In vivo; Vertebrata; Embryo; Chorioallantoic membrane; Structure activity relation; Animal; Inhibitor; Chicken; Aves
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.17.1430

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.