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Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors

文献类型：期刊论文

作者Zhao, Yanmei2; Xu, Lei1; Zhang, Jiankang2,3; Zhang, Mengmeng1; Lu, Jingyi3; He, Ruoyu2; Xi, Jianjun2; Zhuang, Rangxiao2; Li, Jia1; Zhou, Yubo1
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2021
卷号29页码:14
ISSN号0968-0896
关键词Proteasome inhibitor Piperidine Peptidyl Anti-cancer SAR
DOI10.1016/j.bmc.2020.115867
通讯作者Zhuang, Rangxiao(zhuangrangxiao@sina.com) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn)
英文摘要A series of non-covalent piperidine-containing peptidyl derivatives with various substituents at side chains of different residues were designed, synthesized and evaluated as proteasome inhibitors. After proteasome inhibitory evaluations of all the synthesized target compounds, selected ones were tested for their anti-proliferation activities against three multiple myeloma (MM) cell lines. 8 analogues displayed more potent activities than carfilzomib, and the most promising compound 24 showed IC50 values of 0.8 +/- 0.2 nM against 20S proteasome and 8.42 +/- 0.74 nM, 7.14 +/- 0.52 nM, 14.20 +/- 1.08 nM for RPMI 8226, NCI-H929 and MM.1S cell lines, respectively. Additionally, mechanisms of anti-cancer activity of representative compound 24 were further investigated. Apoptosis of RPMI-8226 cells were achieved through accumulating polyubiquitin and inducing the cleavage of caspase and PARP. Besides, half-life in rat plasma of compound 24 was prolonged after optimization, which would be helpful for increasing in vivo activities of this series of derivatives. All the studies confirmed that piperidine-containing non-covalent proteasome inhibitors can be potential leads for anti-MM drug development.
资助项目National Natural Science Foundation of China[81803432] ; Science Technology Department of Zhejiang Province[LGF18H300001]
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:000616051100013
源URL[http://119.78.100.183/handle/2S10ELR8/295761]  
专题新药研究国家重点实验室
通讯作者Zhuang, Rangxiao; Li, Jia; Zhou, Yubo
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Hangzhou Xixi Hosp, Dept Pharmaceut Preparat, Hangzhou 310023, Zhejiang, Peoples R China
3.Zhejiang Univ City Coll, Sch Med, Hangzhou 310015, Zhejiang, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Yanmei,Xu, Lei,Zhang, Jiankang,et al. Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2021,29:14.
APA Zhao, Yanmei.,Xu, Lei.,Zhang, Jiankang.,Zhang, Mengmeng.,Lu, Jingyi.,...&Zhou, Yubo.(2021).Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,29,14.
MLA Zhao, Yanmei,et al."Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 29(2021):14.

入库方式： OAI收割

来源：上海药物研究所

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