新型非共价结合拟肽类蛋白酶体抑制剂的合成及活性评价

Synthesis and Biological Evaluation of Novel Non-covalent Peptidomimetic Proteasome Inhibitors

关键词:  蛋白酶体抑制剂  拟肽  非共价结合  合成  活性评价

Key words:  proteasome inhibitors  peptidomimetic  non-covalent binding  synthesis  biological evaluation

摘要:

目的 设计、合成系列非共价结合拟肽类蛋白酶体抑制剂，并对其进行活性评价。方法 根据非共价结合蛋白酶体抑制剂与蛋白酶体的结合特点，采用氨基酸替换、生物电子等排等经典的药物设计方法，选取邻氯苄胺作为化合物的羧基末端基团，同时在肽骨架结构中引入六元环以增强肽类化合物的稳定性，设计并合成了一系列短肽非共价结合类蛋白酶体抑制剂，并通过体外蛋白酶体活性抑制实验评价该类化合物的活性。结果 共合成了8个具有全新结构的二肽和三肽化合物，其结构经¹H-NMR、ESI-MS确证，该类化合物对蛋白酶体具有中等的抑制活性。结论 肽链的长短及氨基末端不同的取代基对化合物的蛋白酶体抑制活性都有影响，8个化合物在体外对蛋白酶体都具有不同程度的抑制活性。本研究丰富了蛋白酶体抑制剂的结构类型，为该类化合物的深入研究奠定了基础。

Abstract:

OBJECTIVE To design and synthesize a series of non-covalent peptidomimetic proteasome inhibitors, and to evaluate their enzymatic activities. METHODS A series of non-covalent short peptidyl proteasome inhibitors were designed and synthesized with rational drug design strategies such as bioisostere and amino acid replacement based on the binding modes of the non-covalent proteasome inhibitors with the proteasome. 2-Chloride benzyl amine was selected as the carboxyl terminal group, and a six-membered ring was introduced into the peptide skeleton to increase the compounds' stability. All the target compounds were tested for their enzymatic inhibitory activities in vitro. RESULTS Totally 8 novel di-and tripeptidyl analogues were synthesized, which were confirmed by ¹H-NMR and ESI-MS. These target compounds exhibited moderate proteasome inhibitory activities. CONCLUSION The proteasome inhibitory activities of the target compounds are influenced by the length of the peptides and various amino terminal substituents. All the 8 compounds display different degree of proteasome inhibitory activities in vitro. In a word, this study develops series of proteasome inhibitors with new structure type, which will be helpful for the further development of this series of compounds.