Bioacttve oleanene glucuronides obtained from fabaceous plants

Abstract

Oleanene-glucuronide (OG) is defined as an olean-12-ene type triterpene with a C-28 methyl group and a glucuronic acid moiety linked at C-3 of the triterpene. Soyasaponin I is a representative OG. It has been revealed that OGs are widely distributed in fabaceous plants and show several biological activities. As a part of our study on the chemical constituents of fabaceous plants, we have obtained over 191 OGs from 40 fabaceous plants. Furthermore, in the course of our study on hepatoprotective drugs, we devised the conditions for an in vitro assay method using immunologically induced liver injury on primary cultured rat hepatocytes and confirmed hepatoprotective actions of more than 40 OGs and the related compounds. Structure-activity relationships for the sapogenol moiety suggested that the (J-hydroxy group at C-21 would enhance hepatoprotective activity; on the contrary, the hydroxy group at C-23, 24, 29 and 30 could reduce the activity. On the other hand, the free carboxylic acid group at C-28 may mediate cytotoxicity toward liver cells. The structure-hepatoprotective relationships of the sugar moiety suggested that the skeleton with glucuronic acid linked at C-3 was a crucial unit in mediating hepatoprotective activity. In the case of a disaccharide chain boundat C-3, an oxygen-bearing group at C-5″ seems to enhance the hepatoprotective activity. The terminal rhamnopyranosyl group of fabatrioside seems not to be necessary for the activity. Since antiviral activities of OGs against herpes simplex virus type 1 were reported, we also examined antiherpetic activity of some OGs and related compounds. A trisaccharide group shows greater action than a disaccharide group. Monoglucuronide did not show any antiherpetic activity. Further, the sapogenols showed more potent antiherpetic activity than those of their saponins. This structure-activity relationship was completely different from that obtained from hepatoprotective and antiherpetic activities. The mechanism of antiherpetic activitiy of sapogenols might be different from that of saponins. Furthermore, since OGs were known to have not only anti-complementary but also anti-nephritic activities, we tested some OGs toward the classical pathway. Monoglucuronides and diglycosides were most potent then followed by triglycosides, whereas the aglycones exhibited increase of hemolysis. These results indicate that the glucuronic acid moiety is important for expression of anti-complementary activity. The anti-complementary activity of the OGs with a free acid form of glucuronic acid was more potent than that of sodium salt or methylester forms. Furthermore, reduction of the glucuronic acid moiety decreased significantly their activity. The free acid form of the glucuronic acid moiety seemed to contribute to the potency. The hydroxy group at C-24 did not affect the anti-complementary activity except for the methylester forms.