Synthesis and antiproteasomal activity of novel O-benzyl salicylamide-based inhibitors built from leucine and phenylalanine.
作者： Radek Jorda , Jan Dušek , Eva Řezníčková , Karel Pauk , Pratibha P. Magar
DOI: 10.1016/J.EJMECH.2017.04.027
关键词: Cancer cell 、 Ubiquitin 、 Apoptosis 、 Protein degradation 、 Caspase 7 、 Proteasome 、 Biochemistry 、 Bortezomib 、 Molecular biology 、 Chemistry 、 Caspase
摘要: Inhibition of protein degradation is one strategies for suppression uncontrolled proliferation cancer cells. Proteolytic in cells mainly ensured by proteasome and its inhibition bortezomib showed benefit clinical use the treatment multiple myeloma. We report here library antiproteasomal O-benzyl salicylamides built from leucine phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM U266 cell lines, ranging high micromolar to submicromolar GI50 values. The most potent (series 4 6) were further assayed their chymotrypsin-like protease 26S U266 cells. majority inhibited mid-nanomolar concentrations (IC50 57 197 nM) it correlated with cellular potency. In a based assay involving green fluorescence (GFP) fused short degron that rapidly degraded induced accumulation GFP, visualised quantified live-cell imaging. Levels polyubiquitinated proteins U266 cells treated compound 4m also analyzed immunoblotting, revealing typical molecular mass smear ubiquitin conjugates. Finally, apoptotic death was detected biochemically measuring caspases 3 7 lysates immunoblotting caspase 7, substrate poly(ADP-ribose)polymerase, Mcl-1, which all together changes apoptosis. All these observations agreement expected mechanism action confirmed targeting prepared salicylamides.
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