Design, synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid as proteasome inhibitors

Jiankang Zhang; Jiayi Cao; Lei Xu; Yubo Zhou; Tao Liu; Jia Li; Yongzhou Hu

doi:10.1016/j.bmc.2014.04.011

Design, synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid as proteasome inhibitors

Bioorg Med Chem. 2014 Jun 1;22(11):2955-65. doi: 10.1016/j.bmc.2014.04.011. Epub 2014 Apr 13.

Authors

Jiankang Zhang¹, Jiayi Cao², Lei Xu², Yubo Zhou², Tao Liu¹, Jia Li³, Yongzhou Hu⁴

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, 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 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.
⁴ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.

PMID: 24767818
DOI: 10.1016/j.bmc.2014.04.011

Abstract

A series of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome inhibitory activities and selected compounds were tested for their anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and NCI-H929. Among them, eleven compounds exhibited proteasome inhibitory rates of more than 50% at the concentration of 1 μg/mL and nine compounds showed anti-proliferation activities with IC50 values at low micromolar level. Compound 20h displayed the most potent proteasome inhibitory activities (IC50: 0.11 ± 0.01 μM) and anti-proliferation activities with IC50 values at 0.23 ± 0.01 and 0.17 ± 0.02 μM against two tested cell lines. Additionally, the poly-ubiquitin accumulation in the western blot analysis supported that proteasome inhibition in a cellular system was induced by compound 20h. All these experimental results confirmed that β-amino acid can be introduced as a building block for the development of proteasome inhibitors.

Keywords: Anti-cancer; Drug design; Epoxyketone; Proteasome inhibitors; SARs; β-Amino acid.

Publication types

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

MeSH terms

Amino Acids / chemistry*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Epoxy Compounds / chemical synthesis
Epoxy Compounds / chemistry
Epoxy Compounds / pharmacology*
Humans
Ketones / chemical synthesis
Ketones / chemistry
Ketones / pharmacology*
Molecular Structure
Proteasome Endopeptidase Complex / metabolism*
Proteasome Inhibitors / chemical synthesis
Proteasome Inhibitors / chemistry
Proteasome Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Amino Acids
Antineoplastic Agents
Epoxy Compounds
Ketones
Proteasome Inhibitors
Proteasome Endopeptidase Complex