β-内酯类20S蛋白酶体抑制剂的设计、合成与活性研究

泛素－蛋白酶体系统（ubiquitin-proteasome system, UPS）是真核细胞内重要的蛋白质降解途径，维持细胞正常的蛋白质平衡，许多重要的生物过程,如信号转导、细胞周期控制、转录调节、炎症和凋亡是受这一途径调控。20S蛋白酶体已经成为抗肿瘤药物研究的新靶点。本项目是在前期肽类抑制剂的研究基础之上，以β－内酯类抑制剂Omuralide为先导结构，借助于计算机辅助药物设计手段，设计并合成四氢吡咯并β－内酯结构的化合物，并通过酶实验以及细胞实验，对目标化合物的抑制活性以及针对三个活性亚基（β1，β2以及β5）的选择性进行评价,通过活性数据分析，建立三维定量构效关系模型。通过本项目的研究，找到活性更高、结构更加新颖的β－内酯类抑制剂。

The ubiquitin-proteasome system (UPS) in eukaryotes is considered to be critical to the intracellular protein homeostasis. Many important biological processes such as signal transduction, cell cycle control, transcriptional regulation, inflammation, and apoptosis are regulated by this pathway. 20S proteasome has been a new target of the anticancer. Base on the research of peptide inhibitors, Omuralide, which is one of β-lactone inhibitors, is regarded as the lead. Through CADD, the γ-lactam of Omuralide is modified and optimized to C2-substituent tetrahydropyrrole. All the chemicals obtained will be evaluated by enzyme assay and cell-based model. The structure-activity relationship studies of those inhibitors will also be helpful for further providing lead fragments of potential therapeutic targets.