Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors

Bioorg Med Chem. 2021 Jan 1:29:115867. doi: 10.1016/j.bmc.2020.115867.

Yanmei Zhao ¹, Lei Xu ², Jiankang Zhang ³, Mengmeng Zhang ², Jingyi Lu ⁴, Ruoyu He ¹, Jianjun Xi ¹, Rangxiao Zhuang ⁵, Jia Li ⁶, Yubo Zhou ⁷

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; School of Medicine, Zhejiang University City College, Hangzhou 310015, Zhejiang Province, China.
4 School of Medicine, Zhejiang University City College, Hangzhou 310015, Zhejiang Province, China.
5 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China. Electronic address: zhuangrangxiao@sina.com.
6 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.
7 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.

PMID: 33223460 DOI: 10.1016/j.bmc.2020.115867

Abstract

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.

Keywords

Anti-cancer; Peptidyl; Piperidine; Proteasome inhibitor; SAR.

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