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-sol. 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 addn., the compds. 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 concns. that did not affect the related oxidoreductase glutathione reductase (GR). Addnl. complementary information on the enzyme metalation process and potential gold binding sites was obtained through the application of a specific biochem. assay using a thiol-tagging reagent, BIAM (biotin-conjugated iodoacetamide).