Anticancer therapeutics that target selenoenzymes: synthesis, characterization, in vitro cytotoxicity, and thioredoxin reductase inhibition of a series of gold(I) complexes containing hydrophilic phosphine ligands.
Gold(I) complexes bearing water-soluble phosphine ligands, including 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA), and sodium triphenylphosphine trisulfonate (TPPTS), in combination with thionate ligands, were screened for their antiproliferative activities against human ovarian cancer cell lines A2780 either sensitive or resistant to cisplatin. In addition, the compounds were screened for their inhibition of mammalian thioredoxin reductases (TrxR), enzymes that are overexpressed in many tumor cells and contribute to drug resistance. The gold(I)-phosphine complexes efficiently inhibited cytosolic and mitochondrial TrxRs at concentrations that did not affect the related oxidoreductase glutathione reductase (GR). Additional complementary information on the enzyme metallation process and potential gold binding sites was obtained through the application of a specific biochemical assay using a thiol-tagging reagent, BIAM (biotin-conjugated iodoacetamide).
Vergara
Elena
E
Departamento de Química Inorgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain.
Casini
Angela
A
Sorrentino
Francesca
F
Zava
Olivier
O
Cerrada
Elena
E
Rigobello
Maria Pia
MP
Bindoli
Alberto
A
Laguna
Mariano
M
Dyson
Paul J
PJ
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000633:toxicity*; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006046:Gold / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009943:Organophosphorus Compounds / Q000737:chemistry; D010720:Phosphines / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*
C501763:1,3,5-triaza-7-phosphaadamantane; D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D056831:Coordination Complexes; D008024:Ligands; D009943:Organophosphorus Compounds; D010720:Phosphines; D013451:Sulfonic Acids; C400058:triphenylphosphine-3,3',3''-trisulfonic acid; D006046:Gold; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; C044646:phosphine; D000218:Adamantane