New aldehyde and vinylsulfone proteasome inhibitors for targeted melanoma therapy

Abstract: The proteasome is a promising target in cancer therapy. However, it is ubiquitous and its inhibitors cause side effects. To target melanoma cells we synthesized new peptide aldehyde and vinylsulfone inhibitors of the proteasome conjugated to the melanin-targeting ligand (MTL) derived from radiotracer [123I]-N-(2-diethylaminoethyl)benzamide ([123I]BZA) or [125I]-N-(4-dipropylaminobutyl)-4-iodobenzamide ([125I]BZ18). Influence on the cytotoxicity of the benzamide alkyl side chain length and the composition of the amino acid sequence was assessed. Among the conjugates evaluated, compound 16 and 22 presented the highest cytotoxicity (IC50, 0.71 and 0.64 μM respectively), which persisted in the presence of an MTL derived from N-(dialkylaminoalkylenyl)benzamide residue. [Copyright &y& Elsevier]