Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors

Eur J Med Chem. 2017 Jan 27:126:1056-1070. doi: 10.1016/j.ejmech.2016.12.034.

Rangxiao Zhuang ¹, Lixin Gao ², Xiaoqing Lv ³, Jianjun Xi ¹, Li Sheng ², Yanmei Zhao ¹, Ruoyu He ¹, Xiaobei Hu ², Yidan Shao ¹, Xuwang Pan ¹, Shourong Liu ¹, Weiwei Huang ¹, Yubo Zhou ⁴, Jia Li ⁵, Jiankang Zhang ⁶

Affiliations

1 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3 College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang Province, China.
4 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ybzhou@simm.ac.cn.
5 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
6 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China. Electronic address: zjk0125@yeah.net.

PMID: 28027531 DOI: 10.1016/j.ejmech.2016.12.034

Abstract

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 IC₅₀ values 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 their ex vivo and in vivo blood cell Proteasome inhibitory activities. The most potential compound 35 (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 vivo and in vivo activities 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.

Keywords

Anti-cancer; Non-covalent; Peptidyl derivatives; Piperazine or piperidine; Proteasome inhibitors.

Name
Email *

	Sorry, but the email address you supplied was invalid.