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) 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.
Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Firenze, Italy. luigi.messori@unifi.it
Angela
A
Casini
Chiara
C
Gabbiani
Francesca
F
Sorrentino
Maria Pia
MP
Rigobello
Alberto
A
Bindoli
Tilmann J
TJ
Geldbach
Alessandro
A
Marrone
Nazzareno
N
Re
Christian G
CG
Hartinger
Paul J
PJ
Dyson
Luigi
L
Messori
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D017975:Ruthenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017975:Ruthenium Compounds; D013880:Thioredoxin-Disulfide Reductase; D002401:Cathepsin B