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