以氨肽酶N为靶点的N-取代-2,5-吡咯烷二酮类肽的设计合成及活性研究

Design,synthesis and activity study of aminopeptidase N targeted N-substituted-2,5-dioxopyrrolidin peptidomimetics

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。

Aim To find novel aminopeptidase N inhibitors, and to test their inhibitory activities against APN and to study their structures activity relationship. Methods Optically pure L-Asn was used as crude material. The target compounds were synthesized via many steps including α-amino group protection with di-tert-butyl dicarbonate, cyclization, esterification, deprotection, acylation, hydrogenation and hydroximic acid formation. In addition, the interaction between the target compounds and APN active site was analyzed using FlexX docking software. The in vitro APN enzyme assay and structure-activity relationship were also reported. Results Fourteen novel N-substituted-2,5-pyrrolidindione peptidomimetics APN inhibitors were synthesized and the structures were confirmed by ^1H-NMR and ESI-MS. Conclusion All the compounds showed good inhibitory activities against APN, among which 7h, a hydroximic acid derivative, showed potent affinity toward APN, which was highly in line with its FlexX docking result.