Study On Synthesis And Hypoglycemic Activity Of Isoferulic Acid Derivatives

Diabetes mellitus is the most common metabolic disease, resulting from defects in insulin secretion, insulin action, or both. It could cause derangement in carbohydrate, protein and fat metabolism. Long-term defects of insulin produces microvascular and macrovascular complications, composing the main cause of death. It is estimated to affect more than 300 million people worldwide by the year 2025. There are four types of diabetes, among which type 1 and type 2 diabetes are two main forms. Recently, the high morbility of diabetes is still present though type 1 and type 2 hypoglycemic agents have achieved continuously progress in treatment of diabetes. Development of new hypoglycemic agents is urgent needed.Tribe Cimicifugeae is affiliated to Ranunculaceae, with multiple pharmacological activities. Isoferulic acid, one of the main constituents of cimicifuga foetida L., is a kind of 3-phenyl-2-propenoic acid compounds found in natural products. It shows antihyperglycemic activity by decreasing the plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats). The mechanism of plasma glucose lowering effect is related toα1-adrenoceptor as well as opioidμ-receptor. It probably be a fresh acting mechanism of hypoglycemic agents. Structure modification and reconstruction of isoferulic acid can be achieved according to the principle of prodrug and association. It hopefully provide new foundation for development of type 1 hypoglycemic agents.Sixteen target compounds were synthesized by esterification and Knoevenagel-Doebner condensation, basing on isoferulic acid as the lead compound. Among these compounds fourteen are innovative and have not been reported yet. Nine (2E)-3-[4-methoxy-3-[(2E)-(3-phenyl)-2-acryloxy]phenyl]-2-propenoic acid phenolic ester derivatives(L11~L19) were synthesized from isovanillin and cinnamic acid , three (2E)-3-(3-hydroxy-4-methoxyphenyl)-2-propenoic acid phenolic ester derivatives(L21~L23) were synthesized from isovanillin and malonic acid, two (2E)-2-cyano-3-substitutedphenyl-2-acrylamide derivatives(L32,L33) were synthesized from isovanillin and cyanoacetamide. All the new compounds were characterized by means of infrared spectrum (IR), nuclear magnetic resonanc(~1H-NMR) and elemental analysis.The preliminarily IGF-1 mimetic screening model-glucose consume assay in virto have been conducted to all the target compounds, taking insulin as positive agents. It shows that all the target compounds expressed different promoting activity for glucose absorption and hypoglycemic activity to a certain extent at 10μg/ml , except (2E)-3-[4-methoxy-3-[(2E)-(3-phenyl)-2-acryloxy]phenyl]-2-propenoic acid-(4-ethoxycarbonyl)phenolic ester(L15). Among them, L13,L14,L19 and L22 had higher hypoglycemic activity, and the rate of glucose absorption was above 30%. At the same concentration, the glucose absorptivity of insulin is 60.26%.We preliminarily discussed structure-activity relationships of target compounds and found that the structure had effect on activity. The main factors were electricity effect and steric hindrance. Electron attracting group in benzene elevated activity of target compounds. On the opposite, electron donating group lowered activity. Moreover, the volume of substituent group also affect activity of compounds.It needs further study for exact hypoglycemic mechanism of target compounds.