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目的寻找具有氨肽酶N(APN,CD13)抑制活性的新型化合物并测定其抑制氨肽酶N的活性;考察目标化合物与APN活性位点的结合,研究目标化合物与酶的相互作用关系。方法以光学纯的天冬酰胺为原料,经Boc保护、环合、酯化、脱Boc保护、酰化、氢化还原、羟肟酸化等反应合成目标化合物。借助FlexX对接软件,研究目标化合物与APN活性位点的结合情况;采用体外抑酶试验测定目标化合物抑制APN的活性。结果合成了14个未见文献报道的N-取代-2,5-吡咯烷二酮类肽类APN抑制剂,其结构经1H-NMR、MS谱确证。结论目标化合物均对APN/CD13具有一定的抑制活性,其中,化合物7h的活性较好,与计算机对接结果一致。
OBJECTIVE To find novel compounds with inhibitory activity against aminopeptidase N (APN, CD13) and to determine the activity of aminopeptidase N. To study the interaction between target compounds and APN active sites, and to study the interaction between target compounds and enzymes. Methods The optically pure asparagine was used as the starting material to synthesize the target compound by the reaction of Boc, cyclization, esterification, deprotection, acylation, hydrogenation and hydroxamylation. Using FlexX docking software to study the binding of the target compound to the APN active site; the activity of the target compound to inhibit APN was determined by in vitro inhibition of the enzyme assay. Results Fourteen unrelated reports of N-substituted-2,5-pyrrolidinedione APN inhibitors were synthesized and their structures were confirmed by 1H-NMR and MS spectra. Conclusion The target compounds all have certain inhibitory activity on APN / CD13. Among them, the activity of compound 7h is better, which is consistent with the result of computer docking.