一氧化氮供体型双水杨酸酯衍生物的合成及降血糖活性

Synthesis and hypoglycemic activities of nitric oxide-donating salsalate derivatives

目的:研究一氧化氮(NO)供体型双水杨酸酯衍生物的合成和降血糖活性,寻找治疗糖尿病的有效药物。方法:以双水杨酸酯为先导化合物,通过各种连接基团,将硝酸酯类NO供体与双水杨酸酯的2′位羧基连接,分别制得目标物2a-2e、4a、4b、6a、6b。应用GOD-POD法测定目标物增加HepG2细胞耗糖量的作用,应用Griess法测定目标物体外NO释放量。结果:合成了9个目标物,其结构经IR、1HNMR、MS等确证;所有目标物均有不同程度的降血糖活性,其中化合物2a、2b、4b的活性优于双水杨酸酯。结论:NO供体型双水杨酸酯衍生物可能通过释放NO,增强了双水杨酸酯的降血糖活性。其中,化合物2a的活性较强,值得进一步研究。

Aim： To study the synthesis and hypoglycemic activities of nitric oxide-donating salsalate derivatives and search for novel anti-diabetic agents. Methods： Using salsalate as a lead compound, nitrates were incorporated to 2＇-carboxyphenyl of salsalate via a variety of linkers, giving target compounds 2a-2e, 4a, 4b, 6a and 6b. And the compounds＇ activities of increasing the glucose consumption in liver tumor cells were evaluated by GOD-POD assay. In addition, NO-release of the compounds was determined by Griess assay. Results： The structures of all the target compounds were confirmed by IR, MS and ^1H NMR. The screening results demonstrated that all tested compounds exhibited hypoglycemic activities to various extents, especially compound 2a, 2b, 4b showing more potent activity than salsalate did. Conclusion： The hypoglycemic activities of NO-donating salsalate derivatives are probably by NO-release mechanism. Compound 2a is promising for further investigation.