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

Jiankang Zhang; Lixin Gao; Jianjun Xi; Li Sheng; Yanmei Zhao; Lei Xu; Yidan Shao; Shourong Liu; Rangxiao Zhuang; Yubo Zhou; Jia Li

doi:10.1016/j.bmc.2016.10.002

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

Bioorg Med Chem. 2016 Dec 1;24(23):6206-6214. doi: 10.1016/j.bmc.2016.10.002. Epub 2016 Oct 6.

Authors

Jiankang Zhang¹, Lixin Gao², Jianjun Xi¹, Li Sheng², Yanmei Zhao¹, Lei Xu², Yidan Shao¹, Shourong Liu¹, Rangxiao Zhuang³, Yubo Zhou⁴, Jia Li⁵

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 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China. Electronic address: zhuangrangxiao@sina.com.
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.

PMID: 27765408
DOI: 10.1016/j.bmc.2016.10.002

Abstract

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 20nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC₅₀: 1.4±0.1nM) and cytotoxicities with IC₅₀ values at 13.9±1.8nM and 9.5±0.5nM 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.

Keywords: Anti-cancer; Non-covalent; Piperidine; Proteasome inhibitors; SARs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / blood
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Chymotrypsin / antagonists & inhibitors
Drug Design
Drug Stability
Humans
Mice
Oligopeptides / pharmacology
Piperidines / blood
Piperidines / chemical synthesis
Piperidines / pharmacology*
Proteasome Inhibitors / blood
Proteasome Inhibitors / chemical synthesis
Proteasome Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Oligopeptides
Piperidines
Proteasome Inhibitors
carfilzomib
Chymotrypsin