Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors
Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors
复制标题
新型哌嗪或哌啶构建的非共价肽基衍生物作为蛋白酶体抑制剂的探索
DOI：
10.1016/j.ejmech.2016.12.034
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发表时间：
2017
影响因子：
6.7
通讯作者：
Zhang Jiankang
中科院分区：
文献类型：
--
作者：
Zhuang Rangxiao;Gao Lixin;Lv Xiaoqing;Xi Jianjun;Sheng Li;Zhao Yanmei;He Ruoyu;Hu Xiaobei;Shao Yidan;Pan Xuwang;Liu Shourong;Huang Weiwei;Zhou Yubo;Li Jia;Zhang Jiankang
设计、合成了一系列含有新戊基-天冬酰胺残基的新型含哌嗪或哌啶的非共价肽类化合物，并对其作为蛋白酶体抑制剂进行了评价。对所有目标化合物进行了20S蛋白酶体凝乳蛋白酶样活性的筛选，其中15个化合物的IC50值低于10 nM，显示出比carfilzomib更强的活性。随后，测试了最有效的10个类似物对两个多发性骨髓瘤(MM)细胞系RPMI-8226和MM-1S的细胞毒活性。在这些实验的基础上，进一步评估了选定的衍生物对活血细胞蛋白酶体抑制活性的影响。最有潜力的化合物35(蛋白酶体抑制IC50：1.2±0.1nM)具有很强的抗增殖作用(IC50：RPMI-82268.4±100.8nM；MM-1S：6.3±100.8nM)，活性较高的化合物在血浆中的半衰期也延长，这表明通过在多肽骨架上构建六元环，该系列化合物的酶稳定性得到了提高。所有实验都验证了设计理念的正确性，使得这一系列化合物有可能成为探索抗MM新药的先导。
A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC50values lower than 10 nM. Subsequently, the most potent 10 analogues were tested for their cytotoxic activities against two multiple myeloma (MM) cell lines RPMI-8226 and MM-1S. Based on these experiments, selected derivatives were further evaluated for theirex vivoandin vivoblood cell proteasome inhibitory activities. The most potential compound35(proteasome inhibition IC50: 1.2 ± 0.1 nM) with potent anti-proliferation (IC50: RPMI-8226 8.4 ± 0.8 nM; MM-1S: 6.3 ± 0.8 nM),ex vivoandin vivoactivities also had a prolonged half life in plasma, which demonstrated that the enzymatic stabilities of this series of compounds have been improved by constructing a six-membered ring into the peptide skeleton. All the experiments confirmed the correctness of design concept, which made this series of compounds potential leads for exploring new anti-MM drugs.