Synthesis And Activity Investigation Of Oleanolic Acid Derivatives

Oleanolic acid (OA), is a widely distributed, content-rich natural triterpenoids, as free or combined in the form of glycosides, which exists in Diffusa, Hawthorn, lilac, jujube, loquat leaves, wood, Prunella Vulgaris and other plants. OA has a series of biological activities, such as antitumor, anti-HIV, hypoglycemic and liver protective activities, but its relatively weak activities and low bioavailability limit its clinical applications. To improve the biological activity and water-solublity of OA to develop new hypoglycemic drugs with strong activity, good solubility and high oral bioavailability, structural modifications of OA and preliminary biological activity have been investigated in this thesis.At first, nitrogen-containing heterocyclic substituents are introduced in the ring A of OA by Jones Oxidation and Mannich reaction. Six mannich bases are obtained. Their structures are eludicated as 2-((dimethylamino)methy)-3-oxo-olean-12-en-28-oic acid,2-((diethylamino)-methy)-3-oxo-olean-12-en-28-oic acid,2-(pyrrolidin-1-ylmethyl)-3-oxo-olean-12-en-28-oic acid,2-(morpholino-1-methyl)-3-oxo-olean-12-en-28-oic acid,2-(piperidin-1-methyl)-3-oxo-olean-12-en-28-oic acid,2-(thiomorpholino-l-methyl)-3-oxo-olean-12-en-28-oic acid. Secondly, twenty-two esters with amino substituents at C-28 are synthesized from OA and 3-oxo-OA by esterification and amination reactions. All the compounds are characterized by physicochemical properties,1H NMR and MS analysis.In this thesis forty-three OA derivatives are designed and synthesized, of which thirty-four compounds are new compounds. Twenty-nine compounds are tested in vitro for their inhibitory activities against a-glucosidase. Among them, thirteen compounds exhibit a certain degree of inhibitory activity against a-glucosidase. Inhibitory activity of Pyrazolo[4,3-b]oleanane derivative (9) is equal to the parent compound OA. The preliminary analysis of structure-activity relationship reveals:the free carboxyl group at C-28 is indispensable; hydroxyl or other hydrogen-bond donor groups at C-3 contribute to increase inhibitory activity; the introduction of mannich base substitutents at C-2 can also contribute to increase inhibitory activity. The research result can provide evidence for further structural optimization of OA-type a-glucosidase inhibitors.