Metal complexes as inhibitors of the 26S proteasome in tumor cells

The ubiquitin/proteasome pathway is the main mechanism available for eukaryotic cells to eliminate defective proteins and enzymes. Tumor cells -particularly those in solid tumors such as prostate cancer- seem to display increased proteasomal activity associated to cell growth. When such activity is inhibited apoptotic cell death takes place. Thus, the understanding of the chemical mechanisms by which this inhibition occurs is relevant to the development of new therapeutic antineoplastic agents. Here a short review is presented on the synthesis, characterization, and activity of metal-containing species with asymmetric ligands containing the methylpyridin-amino-methylphenol moiety. These complexes were scrupulously investigated structurally and spectroscopically, and have been shown to inhibit the chymotrypsin-like activity of the 20S and 26S proteasome in vitro and in vivo. Recent developments in the understanding of such inhibition are discussed and point out to the influence exerted by ligand substituents, the electronic configurations and charges of the metal ion, and the role of counterions.