Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, UP, India.
Eur J Med Chem. 2013 May;63:162-9. doi: 10.1016/j.ejmech.2013.01.053. Epub 2013 Feb 8.
Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. α-Glucosidase (EC 3.2.1.20) inhibitors interfere with enzymatic action to slow down the liberation of d-glucose from oligosaccharides and disaccharides, resulting in delayed glucose absorption and decreased postprandial plasma glucose levels. In continuation of our drug discovery program on antidiabetic agents, we synthesized novel N-allylated/N-alkylated niacin and α-amyrin (4-9) and lupeol (12-16) hybrids and tested for their α-glucosidase inhibiting activity. Compounds 4-9 showed better activity profile than the marketed α-glucosidase inhibitor i.e. acarbose. Compound 4 possess the highest inhibitory action with IC50 of 5 μM. Kinetic and CD studies revealed that 4 inhibited the α-glucosidase in a noncompetitive manner and caused conformational changes in secondary structure of the enzyme protein.
糖尿病是一种代谢紊乱疾病，其特征是慢性高血糖。α-葡萄糖苷酶（EC 3.2.1.20）抑制剂通过干扰酶的作用来减缓从寡糖和二糖中释放 d-葡萄糖，从而导致葡萄糖吸收延迟和餐后血浆葡萄糖水平降低。在我们继续进行抗糖尿病药物的药物发现计划中，我们合成了新型的 N-烯丙基/N-烷基烟酰胺和 α-香树脂醇（4-9）和羽扇豆醇（12-16）的混合物，并测试了它们对 α-葡萄糖苷酶的抑制活性。化合物 4-9 比市售的 α-葡萄糖苷酶抑制剂即阿卡波糖表现出更好的活性谱。化合物 4 具有最高的抑制作用，IC50 为 5 μM。动力学和 CD 研究表明，4 以非竞争性方式抑制 α-葡萄糖苷酶，并导致酶蛋白二级结构的构象变化。
