Preparation Of Glycyrrhetinic Acid Derivates And Study On Their Antiinflammatory As Ligand Antagonist Of Selectin

Glycyrrhiza uralensis, the main chemical compositions of which include glycyrrhizin, glycyrrhetinic acid, flavonoids, alkaloids et al., has been widely used in medicine, food and chemical industries.Among the above mentioned compositions of glycyrrhiz urzlensis, glycyrrhizin, is fully investigated for its anti-inflammatory activities such as anti-hepatitis B activities, anti-hepatitis C activities and anti-respiratory system infection activities both at home and abroad. However, the long term use of glycyrrhizin can evoke aldosterone-like effects such as hydrops and hypopot assemia ,because of the inhibitory effects of glycyrrhizin on 11 β-hydroxy-steroid dehydrogenase. It has been proved that this adverse effect is correlated with its 11-carbonyl group.glycyrrhizin could be used as an antagonist of the ligand of selectins and developed as new anti-inflammatory drugs because it has similar structures to sLeX, the ligand of selectins. Selectins play important role during inflammation.The binding of selectins with their ligands leads to the extravasation of leukocytes, and the extravasation of a large amount of leukocytes will aggravate the inflammatory reactions and produce adverse effects, so the antagonists of selectins' ligands have anti-inflammatory activities. Five glycyrrhetinic acid derivatives were synthesized with D-glucose, D-galactose, L-fucose, D-lactose, D-amylomaltose and glycyrrhetinic acid. At first, 11-deoxy-glycyrrhetic acid, the glycosyl-receptor, was prepared from glycyrrhetinic acid with environmentally friendly modified Clemmensen reducing reaction. Before the glycosylation of glycyrrhetinic acid with the five saccharides, the saccharides were transfered into the corresponding glycosyl donors. Then the glycosylation of the saccharide donors with allyl 11-deoxy- glycyrrhetinic acid (3) at 3-OH was catalyzed by trimethylsilyl trifluoromethanesulfonate( TMSOTf). The structures of the five derivatives were confirmed as follows:Glycyrrhetinic acid derivatives' effect on adhesion of tumor cells to endothelia cells and platelets were studied. Effects on 11 β-hydroxysteroid dehydroxydrogenase from Hartley guinea pig kidney were studied to evaluate the pseud- aldosterone side effect of glycyrrhetinic acid derivatives.The results and conclusions of the studies are the following:1 Five glycyrrhetinic acid derivatives were prepared. Before the glycosylation of glycyrrhetinic acid with the five saccharides, saccharide trichloroacetimidates donors were prepared.2 The five derivatives manifest dose dependent anti-adhesion activities in the anti-ACC-M/ECV-304 adhesion experiment. Their anti-adhesion activity and inhibition ratio decreased with the order of 7d>7c>7e>7a>7b.3 The five derivatives exhibit dose dependent anti-adhesion activities in the anti-ACC-M/platelets adhesion experiment. Their anti-adhesion activity and inhibition ratio decreased with the order of 7d>7e>7c>7a>7b.4 In the exercise of effects on 11 β-hydroxysteroid dehydroxydrogenase of glycyrrhetinic acid derivatives from Hartley guinea pig kidney, the data showed that their effects on 11β- hydroxysteroid dehydroxydrogenase was less potent than glycyrrhizin.