Design, Synthesis and Evaluation of Substituted Aryl-2-Nitrovinyl Derivatives as Small Molecules Proteasome Inhibitors

Based on the existing structure activity relationship for proteasome inhibitors, a number of substituted aryl-2-nitrovinyl derivatives have been synthesized as Michael acceptor and their cytotoxicity and proteasome inhibitory effects were evaluated on two cancer cell lines. Compound 2d exhibited IC50 values of 0.71 and 17.79 μM comparable to bortezomib against MCF-7 and PC-3, respectively. The results show that the electronic properties and steric hindrance can affect the interaction of these small molecules with their receptor at the active site of the enzyme while the presence of CH2OH group on α-carbon of Michael acceptor is favorable, and para substitution of OMe on phenyl ring of β-carbon can increase the inhibitory potencies.
Molecular docking studies confirm our experimental findings about mode of binding of our compounds with 20S proteasome.