The role of peripheral substituents in modulating the antiproteasome potential of porphyrins.

The main function of the proteasome - an enzymatic complex located in the nucleus and the cytoplasm - is to degrade unneeded or misfolded proteins. To emphasize its essential role in numerous cellular processes, inhibition of the proteasome has been investigated in the treatment of diverse diseases including cancer. Bortezomib and the other proteasome inhibitors (PIs) that are currently under clinical investigation, bind to the catalytic sites of proteasomes and are competitive PIs. It’s conceivable that proteasome inhibitors that act through a noncompetitive mechanism might overcome some forms of bortezomib resistance. Thus, there is a crying urgency to develop new noncompetive PIs with an improved pharmacological profile. [1] Cationic porphyrins have versatile chemistry and are reversible proteasome inhibitors with a putatively competitive mechanism. [2] The lack of information about the relationship between the molecular structure of cationic porphyrins and their antiproteasome activity is a major drawback in the establishment of novel therapeutic strategies based on the development of multi-target photosensitizers. Here, we report the antiproteasomal activity and the inhibition mechanism of new molecules obtained by conjugating the porphyrin core to: i) phenylpyridines, ii) peptide apidaecin (MTPyP-APi); iii) or spermines, a polyamine occurring in many human tissues. Our results evidence that the number, the nature of peripheral substituents may regulate either the inihibitor potency (IC50) and the inhibition mechanism.