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

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

Authors :
Zhang J
Gao L
Xi J
Sheng L
Zhao Y
Xu L
Shao Y
Liu S
Zhuang R
Zhou Y
Li J
Source :
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2016 Dec 01; Vol. 24 (23), pp. 6206-6214. Date of Electronic Publication: 2016 Oct 06.
Publication Year :
2016

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 IC <subscript>50</subscript> less than 20nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC <subscript>50</subscript> : 1.4±0.1nM) and cytotoxicities with IC <subscript>50</subscript> 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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1464-3391
Volume :
24
Issue :
23
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry
Publication Type :
Academic Journal
Accession number :
27765408
Full Text :
https://doi.org/10.1016/j.bmc.2016.10.002