Design, synthesis and docking studies of novel dipeptidyl boronic acid proteasome inhibitors constructed from ??- and ??-amino acids.
A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from ??- and ??-amino acids were designed and synthesized. Their structures were elucidated by (1)H NMR, (13)C NMR, LC-MS and HRMS. These compounds were evaluated for their ?5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic ... acid inhibitors composed of ??-amino acids were as active as bortezomib. Interestingly, the activities of those derived from ??-amino acids lost completely. Of all the inhibitors, compound 22 (IC50=4.82 nM) was the most potent for the inhibition of proteasome activity. Compound 22 was also the most active against three MM cell lines with IC50 values less than 5 nM in inhibiting cell growth assays. Molecular docking studies displayed that 22 fitted very well in the ?5 subunit active pocket of proteasome.
Mesh Terms:
Amino Acids, Boronic Acids, Cell Line, Tumor, Cell Proliferation, Dipeptides, Dose-Response Relationship, Drug, Drug Design, Humans, Molecular Docking Simulation, Molecular Structure, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Structure-Activity Relationship
Amino Acids, Boronic Acids, Cell Line, Tumor, Cell Proliferation, Dipeptides, Dose-Response Relationship, Drug, Drug Design, Humans, Molecular Docking Simulation, Molecular Structure, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Structure-Activity Relationship
Bioorg Med Chem Lett
Date: Apr. 15, 2016
PubMed ID: 26965867
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