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

Diabetes mellitus is a metabolic disordered disease caused by lacking of insulin secretion capacity within the body, or obstacles of biological effect, clinically in general is characterized by high blood sugar. With the continuous development of economy, people’s lifestyles and habits gradually changed, leading to a higher incidence of diabetes. Ursolic acid (UA,3β-hydroxy-urs-12-en-28-oic acid,1) is a well-known pentacyclic triterpenes, widely existed in Chinese herbal medicine and plant kingdom which possessed interesting bioactivities, such as anti-tumor, anti-bacterial, anti-inflammatory, anti-malaria, etc. Studies have shown that UA has a positive effect on lowing blood glucose levels and curing diabetic complications in diabetic mice. UA is constituted by a rigid pentacyclic sketelon, which is highly hydrophobic and makes UA poorly water-soluble, limits its bioavailability and therapeutic applications in clinical medicine. Currently, most research focus on the hydroxyl group of C-3 position and carboxy group of C-28 position of UA in the introduction of hydrophilic carboxyl groups to improve their water-soluble in order to better study the biological activity and bioavailability of UA and its derivatives. But there are few applications focused on the anti-diabetic properties and diabetic complications of UA derivatives.The main purpose of this paper is to find natural ursolic acid which own hypoglycemic activity as precursor compound. In order find innovative drug lead compounds which are efficient and few side effects, following the organic chemistry as the theoretical guidance, through the computer aided simulation technology, chemical method and biological activity assay.In this paper, through the use of molecular modeling software selected compound with a-glucosidase which has shown high binding capacity, with the method of esterification, acylation, amidation, hydrolysis and hydrogenation, a series of ursolic acid derivatives were synthesized, and their structures were confirmed. The author successfully accumulated around 19 compounds, including 15 new compounds. The activity of the synthesized compounds against a-glucosidase was determined in vitro. The results suggested that all compounds have significant inhibitory activity, especially compounds 3,4,10 and 11, the IC50 values of which were lower than UA and positive control. The kinetic inhibition studies reveal that compound 3 and 4 were mix-type inhibitors while compound 10 and 11 were non-competitive inhibitors. It had important significance for these finding supports the use of these compounds as a potential source for the discovery of high efficiency and reducing hyperglycemia active medicine for future therapy of diabetes and complications.