Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors

doi:10.1016/j.bmc.2020.115867

	Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors
	Zhao, Yanmei 1; Xu, Lei 2; Zhang, Jiankang 1,3; Zhang, Mengmeng 2; Lu, Jingyi 3; He, Ruoyu 1; Xi, Jianjun 1; Zhuang, Rangxiao 1; Li, Jia 2; Zhou, Yubo 2
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2021
卷号	29 页码:14
关键词	Proteasome inhibitor Piperidine Peptidyl Anti-cancer SAR
ISSN号	0968-0896
DOI	10.1016/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
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295761]
专题	中国科学院上海药物研究所
通讯作者	Zhuang, Rangxiao; Li, Jia; Zhou, Yubo
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, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, 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.