新型β-肽环氧酮类蛋白酶体抑制剂的合成与活性评价

Synthesis, Biological Evaluation of Novel β-Peptidyl Epoxyketone Proteasome Inhibitors

关键词:  蛋白酶体抑制剂  β-肽环氧酮  合成  活性评价

Key words:  proteasome inhibitors  β-peptidyl epoxyketone  synthesis  biological evaluation

摘要:

目的 设计合成新型的β-肽类蛋白酶体抑制剂，并对其活性进行评价。方法 根据先导化合物Carfilzomib与蛋白酶体的作用方式，保留其与蛋白酶体结合的关键环氧酮片段，并结合β-氨基酸的特点，采用氨基酸替换、生物电子等排等药物设计的方法，设计一类结构新颖的蛋白酶体抑制剂；采用缩合、氧化、还原等反应，合成系列目标化合物；通过体外酶抑制活性实验检验化合物活性。结果 合成了8个结构新颖的β-肽环氧酮类衍生物，化合物结构经1H-NMR、ESI-MS确证，部分化合物体现了一定的蛋白酶体抑制活性。结论 β-氨基酸作为一种重要的α-氨基酸替换结构，有望能够丰富短肽类蛋白酶体抑制剂的结构类型。

Abstract:

OBJECTIVE To discover novel β-peptidyl epoxyketone proteasome inhibitors, evaluate their enzymatic activities. METHODS According to the binding interactions of lead compound Carfilzomib with proteasome, the epoxyketone group of Carfilzomib was retained in the drug design. A series of novel proteasome inhibitors were designed by combining the retained epoxyketone group, β-amino acid using rational drug design strategies such as amino acid, bioisostere replacement. These compounds were synthesized through condensation, oxidation, reduction reactions, were tested for their enzymatic activities in vitro. RESULTS Totally 8 novel β-peptidyl epoxyketone analogues were synthesized, confirmed by ¹H-NMR, ESI-MS, which exhibited moderate proteasome inhibitory activities. CONCLUSIONS β-Amino acid, which is an important α-amino acid replacement, is anticipated to enrich the structure diversity of proteasome inhibitors.