Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors

doi:10.1016/j.bmc.2016.10.002

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	Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors
	Zhang, Jiankang 1; Gao, Lixin 2; Xi, Jianjun 1; Sheng, Li 2; Zhao, Yanmei 1; Xu, Lei 2; Shao, Yidan 1; Liu, Shourong 1; Zhuang, Rangxiao 1; Zhou, Yubo2
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2016-12-01
卷号	24 期号:23 页码:6206-6214
关键词	Proteasome inhibitors Piperidine Non-covalent Anti-cancer SARs
ISSN号	0968-0896
DOI	10.1016/j.bmc.2016.10.002
文献子类	Article
英文摘要	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 IC50 less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4 +/- 0.1 nM) and cytotoxicities with IC50 values 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 compounds 24 and 27-29 demonstrated 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. (C) 2016 Elsevier Ltd. All rights reserved.
资助项目	Key Development Program of the Hangzhou Science and Technology Committee[20152013A03] ; Hangzhou Science and Technology Committee[20150733Q49] ; National Natural Science Foundation of China[81473244]
WOS关键词	CHYMOTRYPSIN-LIKE ACTIVITY ; HUMAN 20S PROTEASOME ; CANCER-THERAPY ; PROTEOLYTIC PATHWAY ; CRYSTAL-STRUCTURE ; MULTIPLE-MYELOMA ; APPROVAL ; SERIES ; CARFILZOMIB ; COMPLEX
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000389519600009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275784]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室药物安全性评价中心
通讯作者	Zhuang, Rangxiao; Zhou, Yubo; Li, Jia
作者单位	1.Hangzhou Xixi Hosp, Dept Pharmaceut Preparat, Hangzhou 310023, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Jiankang,Gao, Lixin,Xi, Jianjun,et al. Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2016,24(23):6206-6214.
APA	Zhang, Jiankang.,Gao, Lixin.,Xi, Jianjun.,Sheng, Li.,Zhao, Yanmei.,...&Li, Jia.(2016).Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,24(23),6206-6214.
MLA	Zhang, Jiankang,et al."Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 24.23(2016):6206-6214.