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

Abstract

A series of ruthenium(II)-arene (RAPTA) compounds 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 compounds 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 compounds toward solid metastatic tumors also correlates to the observed trends. Notably, docking studies of the interactions of representative RAPTA compounds 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 compounds and the computed stability of the corresponding cat B/RAPTA adducts.

Interactions of arene ruthenium metallaprisms with human proteins

“…These complexes selectively bind to proteins or inhibit enzymes known to be overexpressed in many types of cancer. 7,[9][10][11][12][13] To date, much work has been done to elucidate the mode of action of various ruthenium-based drug candidates, 14,15 but the way they exert their antitumoural or antimetastatic effects is not yet fully understood, even for NAMI-A and NKP-1339, which have successfully completed clinical trials. 14,[16][17][18] By analogy with platinum complexes, it was originally assumed that DNA binding was the main reason for the anticancer activity of ruthenium complexes.…”

Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound

“…Moreover, protein-bound metallofragments potentially represent the actual active anticancer species present in vivo-rather than simple drug activation products-provided that transfer of the metal among specific binding sites is kinetically favoured [18]. In addition, metallation of specific amino acid residues, affecting the function of biologically crucial proteins through the formation of strong coordination (covalent) bonds, might play a relevant role in the overall toxicological profile of metalbased drugs [19][20][21]. Indeed, a number of reviews on metallodrug-protein interactions have been published that explore various aspects of their relevance to anticancer activity [22][23][24].…”

Synthesis of Novel Palladacycles Inhibitors of the Cathepsin B Activity and Antitumoral Agents

“…This study are aiming to address some complexes can be used as biological probes for proteins and biomolecules, e.g. cysteine, selenocysteine proteases [73][74][75]. All these exciting aspects of palladacycle chemistry will be divulged in due course.…”

“…Compounds were dissolved at 5 mg ml-1 in sterile DMSO, and further diluted with the appropriate complete cell culture medium. After 72 h, cell viability was assessed using MTT(Sigma), also following published protocols [20,[72][73][74].…”