Emerging Protein Targets for Anticancer Metallodrugs: Inhibition of Thioredoxin Reductase and Cathepsin B by Antitumor Ruthenium(II)-Arene Compounds

A series of ruthenium(II)-arene (RAPTA) compds. were evaluated for their ability to inhibit thioredoxin reductase (either cytosolic or mitochondrial) and cathepsin B, two possible targets for anticancer metallodrugs. In general, inhibition of the thioredoxin reductases was lower than that of cathepsin B, although selected compds. were excellent inhibitors of both classes of enzymes in comparison to other metal-based drugs. Some initial structure-activity relationships could be established. On the basis of the obtained data, different mechanisms of binding/inhibition appear to be operative; remarkably the selectivity of the ruthenium compds. toward solid metastatic tumors also correlates to the obsd. trends. Notably, docking studies of the interactions of representative RAPTA compds. with cathepsin B were performed that provided realistic structures for the resulting protein-metallodrug adducts. Good agreement was generally found between the inhibiting potency of the RAPTA compds. and the computed stability of the corresponding cat B/RAPTA adducts.