Inhibitory effects of tetrandrine and related synthetic compounds on angiogenesis in streptozotocin-diabetic rodents.
Structure-activity relationships of tetrandrine, isolated from a Kampo medicine, Stephania tetrandrae S. MOORE (root), and related synthetic compounds, were investigated in in vitro fetal bovine serum (FBS)-stimulated angiogenesis of cultured choroids in streptozotocin-diabetic Wistar rats, and air-pouch granuloma angiogenesis in vivo in diabetic mice. Tetrandrine, KS-1-1 (6,7-dimethoxy-1-[[4-[5-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl-2-methoxy]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahyd roisoquinoline), and KS-1-4 (6,7-dimethoxy-1-[[4-[4-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroiso quinolinyl)methyl]phenoxy]benzyl]-2-methyl-1,2,3,4-tetrahydroisoquino line), potently inhibited choroidal angiogenesis and air-pouch granuloma angiogenesis in the diabetic state. Their inhibitory effects on diabetic choroids were greater than those on normal choroids. Among these compounds, KS-1-4 inhibited only diabetic angiogenesis. These compounds significantly inhibited FBS-stimulated tube formation in vascular endothelial cells from normal rats. Tetrandrine and KS-1-4, but not KS-1-1, inhibited vascular endothelial growth factor- and platelet-derived growth factor-BB-stimulated angiogenesis in normal choroids. The bis[tetrahydroisoquinoline] moiety, connected by oxy-bis[phenylenemethylene] and 2,2'-dimethyl groups in tetrandrine, contributes to the inhibition of diabetic choroidal angiogenesis. KS-1-4 may be a candidate for anti-choroidopathy and retinopathy drugs in the diabetic state.
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000077214:Becaplermin; D044182:Benzylisoquinolines; D001769:Blood; D002478:Cells, Cultured; D046508:Culture Techniques; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D004365:Drugs, Chinese Herbal; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors