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

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.

• Authors: Jiankang Zhang, Jiayi Cao, Lei Xu, Yubo Zhou, Tao Liu, Jia Li, Yongzhou Hu
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 11 Pg. 2955-65 (Jun 01 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 24767818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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