摘要：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-tetrahydroisoquinolinyl)methyl-2-methoxy]phenoxy]benzol]-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline), and KS-1-4 (6, 7-dimethoxy-1-[[4-[4-(6, 7-dimethoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinolinyl)methyl]phenoxy]benzyl]-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline), 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'-diemthyl groups in tetrandrine, contribues to the inhibition of diabetic choroidal angiogenesis. KS-1-4 may be a candidate for anti-choroidopathy and retinopathy drugs in the diabetic state.
