Structure-Activity Relationships of Polyhydroxyursane-type Triterpenoidson the Cytoprotective and Anti-inflammatory Effects

Eleven polyhydroxyursane triterpenoids (PHUTs) were tested to determine their cytoprotective, immunosuppressive and anti-inflammatory effects. To compare the bioactivities of 19α -hydroxyursane-type triterpenoids {23-hydroxytormentic acid (6), its methyl ester (7), tormentic acid (8), niga-ichigoside F 1 (9),euscaphic acid (10) and kaji-ichigoside F 1 (11)} of the Rosaceae crude drugs (Rubi Fructus and Rosa rugosae Radix) with PHUTs possessing no 19α−hydroxyl of Centella asiatica (Umbelliferae), the four PHUTs, asiaticoside (1), madecassoside (2), asiatic acid (3), and madecassic acid (4) were isolated from C. asiatica and 23-hydroxyursolic acid (5) from Cussonia bancoensis. Cytoprotective effects were assessed by measuring cell viabilities against cisplatin-induced cytotoxocity in LLC−PK 1 , cells (proximal tubule, pig kidney) to determine whether these agents have protective effects against nephrotoxicity caused by cisplatin. The inhibitory effect of 11 PHUTS on nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) were evaluated by measuring nitrite accumulation in lipopolysaccharide (LPS)-induced macrophage RAW 264.7 cells, and their anti-inflammatory effects were tested in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema model. Six MHUTs (compounds 1, 2, 4, 6, 10, and 11) exhibited higher cell viabilities during cisplatin-induced cytotoxicity testing even at a concentration of 200μg/ml than cisplatin only-treated group, suggesting that ese compounds have the potentcytoprotective efffcts. Compounds 1 and 3 of the C. asiatica and niga-ichigoside F 1 exhibited no inhibitory effect on NO and/or PGE 2 production whereas other PHUTs produced mild to significant NO and/or PGE 2 production.The four compounds (2, 5, 9, and 10) potently inhibited mouse ear edema induced by TPA whereas two compounds (1 and 3) had no activity in this test. These results suggest that many PHUTs are potentchemopreventives. Structure-activity relationship (SAR) was also discussed in each assay with regard to the significant role of OHs at the position of 2, 3, 6, 19, and 23 and to the glycoside linkage at the 28-carboxyl. KCI Citation Count: 1