Synthesis, in Vitro and in Vivo Biological Evaluation, Docking Studies, and Structure−Activity Relationship (SAR) Discussion of Dipeptidyl Boronic Acid Proteasome Inhibitors Composed of β-Amino Acids

摘要: A series of novel dipeptidyl boronic acid proteasome inhibitors composed β-amino acids were synthesized, in vitro and vivo biologically evaluated, theoretically modeled for the first time. From screened racemic compounds enzyme, 4i was most active. The IC50 value its pure enantiomer 4q 9.6 nM, 36-fold more active than isomer 4p as marketed bortezomib inhibiting human 20S proteasome. This candidate also showed good activities with values nearly less 5 μM against several solid hematologic tumor cell lines. Safety evaluation zebrafish Sprague−Dawley (SD) rats that toxic bortezomib. Pharmacokinetic profiles suggested a plasma exposure longer half-life Docking results indicated interacted similar way