Synthesis Of Ursolic Acid Derivatives And Their Activities On α-glucosidase Inhibition

Diabetes mellitus is a chronic disease that occurs when the pancreas does not produce sufficient insulin or when the body cannot use it effectively, thereby leading to an increased blood glucose concentration. Over the last century, the ever-changing lifestyle of the population has resulted in a dramatic increase in the incidence of diabetes.Pentacyclic triterpenes and their derivatives are ubiquitous in the plant kingdom and possess interesting bioactivities, such as antitumor, anti-HIV, antibacterial, antimalarial, etc. Ursolic acid (UA,3β-hydroxy-urs-12-en-28-oic acid,1) is a well-known pentacyclic triterpene that has been reported to possess a wide range of biological activities. It serves as one of the major effective components of many traditional Chinese herbal medicines. Studies have shown that UA has a positive effect on lowing blood glucose levels and curing diabetic complications in diabetic mice. However, UA has a very low water solubility, which limits its bioavailability and therapeutic applications in clinical medicine. To improve its activity and bioavailability, chemical modification of UA at the3-OH or17-COOH positions has recently been widely investigated. But there are few studies focused on the anti-diabetic properties of UA derivatives.In this study, with the method of esterification, oxidation, amidation, hydrolyzation, a series of ursolic acid derivatives were synthesized, and their structures were confirmed. The activity of the synthesized compounds against α-glucosidase was determined in vitro. The results suggested that all compounds have significant inhibitory activity, especially compounds3-5,8,10and14-22, the IC50values of which were lower than UA and positive control. Kinetic studies were performed to determine the mechanism of inhibition by compounds3-5and8. The kinetic inhibition studies indicated that compound3was a non-competitive inhibitor, and the inhibition constant Ki was calculated to be2.67±0.19μM. Moreover, the kinetic inhibition studies of compounds4,5and8demonstrated that they were mixed-type inhibitors. Furthermore, the actual pharmacological potentials of synthesized compounds3and4were demonstrated by the reduction of postprandial blood glucose levels in normal Kunming mice. The hypoglycemic effects of these compounds were more evident30and60min after maltose ingestion (P＜0.05), which was similar to the effect displayed by the positive control, acarbose. In addition, there is a close relationship between oxidative stress and diabetes. Therefore, total antioxidant capacity of all compounds were also measured by the Oxygen Radical Absorption Capacity (ORAC) method, all of tested derivatives had lower antioxidant capacity.