Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors
Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors
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新型非共价哌啶肽蛋白酶体抑制剂的设计、合成及生物学评价
DOI：
10.1016/j.bmc.2016.10.002
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发表时间：
2016
影响因子：
3.5
通讯作者：
Li Jia
中科院分区：
文献类型：
--
作者：
Zhang Jiankang;Gao Lixin;Xi Jianjun;Sheng Li;Zhao Yanmei;Xu Lei;Shao Yidan;Liu Shourong;Zhuang Rangxiao;Zhou Yubo;Li Jia
设计、合成了一系列新型的非共价哌啶二肽类化合物，并对其作为蛋白酶体抑制剂进行了评价。检测了所有目标化合物的蛋白酶体胰凝乳酶样活性，并对所选的衍生物进行了抗多发性骨髓瘤(MM)细胞系RPMI8226和MM-1S增殖活性的评价。在所有化合物中，有8个化合物具有显著的蛋白酶体抑制活性，其IC50小于20 nM，其中4个化合物的IC50高于阳性对照化合物Carfilzomib。化合物28对RPMI8226和MM-1s具有最强的蛋白酶体抑制活性(IC50：1.4±0.1nM)和细胞毒作用，IC50值分别为13.9nM±31.8nM和9.5nM±100.5nM。此外，化合物24和27-29的体外血细胞蛋白酶体抑制活性表明，全血中的酶代谢是可以耐受的。所有这些实验都证实了含有哌啶的非共价蛋白酶体抑制剂是探索新的抗癌药物的潜在线索。
A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound28displayed the most potent proteasome inhibitory activity (IC50: 1.4 ± 0.1 nM) and cytotoxicities with IC50values at 13.9 ± 1.8 nM and 9.5 ± 0.5 nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds24and27–29demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs.