Synthesis of l-cysteine-based boron compounds and their evaluation as proteasome inhibitors

Abstract

Amides, boronic acids and ester derivatives from L-cysteine were synthesized via a simple, short and inexpensive synthetic route, in order to achieve a novel class of inhibitors for the 20S proteasome. IC₅₀ values of up to 52 μM were obtained with L-cysteine boronic ester derivatives, which also exhibited reversible inhibition. Assays with lysates and whole cell of NIH/3T3 fibroblast NIH Swiss mice were also performed using the boron compound S-benzyl-cysteine-(3-phenyl)boronic ester. This study revealed that for whole cells and lysed cells, the boron compound inhibited proteasome with the same level of efficiency as for the free enzyme (residual enzyme activity for whole cells: 31.5%; lysed cells: 43%; and free enzyme: 43%). Molecular modeling studies were also applied to understand the interactions between the synthesized compounds and the 3-D proteasome structure.