Design,Synthesis And Biological Activity Evaluation Of Novel PTP1B Inhibitors Based On Hypoglycemic Natural Products

Diabetes mellitus(DM) is the most serious and prevalent metabolic disorders worldwide,complications of which can decrease significantly the quality of life and contribute to premature death. In patients with diabetes, the type 2 diabetes(T2D) proportion of about 95%.Resistance to insulin is a predominant pathophysiological factor of type 2 diabetes(T2D).Insulin sensitization agent can improve the insulin stimulation target organization’s ability to use glucose thereby reducing blood sugar, become a focus in the study of type 2diabetes drugs. The past decade has seen the emergence of several new classes of anti-T2 D drugs, however, the only insulin sensitizers currently on the market were biguanides and the TZDs. Therefore, new insulin sensitizers would undoubtedly fill a much needed void in treatment options for T2 D patients who no longer respond to biguanides or cannot use pioglitazone due to its contraindications.Till date, mounting biochemical and pharmacological evidences established that PTP1 B is an important negative factor of insulin and leptin signal. To inhibit the activity of PTP1 B by PTP1 B inhibitors, thereby effectively treating Type II diabetes and obesity. Mimetics of p Tyr are starting points for the design of competitive PTP1 B inhibitors. However, most active-site-directed p Tyr mimetics are generally have limited cell membrane permeability.Therefore, several structure modification strategies have been used to increase the cell permeability to develop PTP1 B inhibitors with good bioavailability.Pentacyclic triterpenoid have long been studied as potential PTP1 B inhibitors, which is having a PTP1 B inhibition in vivo activity of development of new drugs and lead compounds opportunities. Although researchers have structural modifications of pentacyclic triterpenoid compounds and develop potential PTP1 B inhibitory activity of compounds, but there is no denying the fact that pentacyclic triterpenoids as drug development has its birth defects, such as molecular weight, poor lipid-water distribution coefficient, easy through the cell membrane,the oral drug low bioavailability, widespread activity has low selectivity, structural modification space is very limited. Therefore, to solve the drawbacks of the various medicines such compounds, it must be reasonable structural modification and simplify the structure.In this paper, pentacyclic triterpenoid derivative G were used as lead compound. lead compound G and PTP1 B binding mode were be analyzed, and then with the aid of computer-aided design tools, the structure of the lead compound G were to simplify and optimize the final design of the target compound T. In order to get the target compounds, we explore the specific reaction conditions based on the analysis of the structure and related literatures and design a practical synthetic rout. Finally,we successfully synthesized four rosin acid derivatives and nine new structure target compounds. At the same time we screenthe anti-PTP1 B activity for the nine new compounds, Wherein the compound AA-1 has a considerable PTP1 B inhibitory activity with lead compound G. Preliminary structure-activity relationship showing: between a and c is part of the two carbon inhibitory effect is optimal;between b and c of the connection portion in a manner superior to ether ester way to connect;when between b and c portions manner ester when connecting a carboxyl group at the ortho position while suppressing effect is optimal, while between b and c portion of ether carboxyl connected in the para position when the inhibitory effect is optimal. We hope this study can be found in more potential novel PTP1 B inhibitors and to develop new diabetes treatment insulin-sensitizing effect of the drug to provide a reference.