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二酰基甘油酰基转移酶(DGAT)作为甘油三酯合成的唯一限速酶,成为治疗肥胖以及其他代谢综合征的重要靶标.利用从具有DGAT1抑制活性的天然产物aphadilactone C分子中重要内酯环与进入临床研究的2-((1R,4R)-4-(4-(4-氨基-5-氧亚基-7,8-二氢嘧啶[5,4-f][1,4]氧氮杂-6(5H)-基)苯基)环己基)乙酸(PF-04620110),2-((1R,4R)-4-(4-(6-氨甲酰基-3,5-二甲基对二氮杂苯-2-基)苯基)环己基)乙酸(AZD-7687)分子中杂环单元的重新组合,设计合成了化合物5~8,以此来验证aphadilactone C中内酯环单元是否与已知DGAT1抑制剂中的环己基乙酸部分相等同.最终的活性测试结果显示,化合物5~8并不具有DGAT1的抑制作用.天然产物aphadilactone C的DGAT抑制机制值得深入研究.
Diacylglycerol acyltransferase (DGAT), as the only rate-limiting enzyme in the synthesis of triglycerides, has become an important target for the treatment of obesity and other metabolic syndromes.Using the important lactone ring from the natural product aphadilactone C molecule with DGAT1 inhibitory activity and Into the clinically studied 2 - ((1R, 4R) -4- (4- (4-amino-5-oxo-7,8- dihydropyrimido [5,4-f] [1,4] (4- (6-carbamoyl-3,5-dimethyl) phenyl) cyclohexyl) acetic acid (PF-04620110) 2-yl) phenyl) cyclohexyl) acetic acid (AZD-7687) was synthesized and the compounds 5-8 were designed and synthesized to confirm that the lactone ring in aphadilactone C The results of the final activity test showed that compounds 5 to 8 do not have the inhibitory effect on DGAT 1. The natural product of aphadilactone C DGAT inhibition mechanism deserves further study.