Design, Synthesis, Biological Evaluation, and Structure−Activity Relationship (SAR) Discussion of Dipeptidyl Boronate Proteasome Inhibitors, Part I: Comprehensive Understanding of the SAR of α-Amino Acid Boronates

摘要: New series of dipeptidyl boronate inhibitors 20S proteasome were designed and synthesized. The comprehensive understanding the SAR was obtained by utilizing variation four substituents. From screened compounds in enzyme, novel 49 50 identified to be highly potent druglike candidates with IC50 values 1.2 1.6 nM, respectively, which showed better activities than drug bortezomib on market. Two hematologic human tumor cell lines, HL-60 U266, significantly sensitive both nearly same potency as standard less 10 nM. But for most eight solid more value range 9.8−70 activity evaluation stereoisomers that changing R-isomers S-isomers greatly reduced even induced inactivity.