A Soluble Bis-Chelated Gold(I) Diphosphine Compound with Strong Anticancer Activity and Low Toxicity

Abstract

Gold-containing compounds have shown anticancer potential, but their clinical applications have been severely limited by poor stability and high toxicity in vivo. Here, we report a novel soluble bis-chelated gold(I)-diphosphine compound (GC20) with strong anticancer activity and low toxicity. GC20 shows strong antiproliferation potency against a broad spectrum of cancer cell lines including cisplatin-resistant cancer cells (IC50 ≈ 0.5 μM) and significantly reduces tumor growth in several tumor xenografts in mouse models at doses as low as 2 mg/kg. Studies of its mechanism revealed that GC20 specifically inhibits the enzymatic activity of thioredoxin reductase by binding to selenocysteine residue, without targeting other well-known selenol and thiol groups contained in biomolecules. Remarkably, in animal studies GC20 was shown to be well tolerated even at the high dose of 8 mg/kg. Our results strongly suggest that GC20 represents a promising candidate for the development of novel anticancer drugs.

Gold Complexes for Therapeutic Purposes: an Updated Patent Review (2010-2015)

“…It should be underlined that the body weight of all animals in the study never decreased. Similar results were observed in other xenografts, including murine Lewis lung cancer, human LS174T colon carcinoma and murine hepatocellular carcinoma H22 [88].…”

“…Concerning the gold(I) compounds, only the patent n. 8 describes some toxicological studies [85,88]. In particular, the acute toxicity of compound XVIII (Table 1) was studied in rats per os.…”

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

“…The in vitro IC 50 of 82 for TrxR is about 247.60 nM. In addition, the authors discovered that rapid dilution of the 82 /TrxR mixture leads to complete recovery of TrxR activity, which suggests a reversible inhibition . Jortzik et al.…”

Synthesis, Characterization, andin vitroCytotoxicity of Gold(I) Complexes of 2-(Diphenylphosphanyl)ethylamine and Dithiocarbamates

“…Sadler , Berners‐Price and co‐workers carried out the cytotoxic studies of gold(I) complexes with bisphosphine ligands, R 2 P(CH 2 ) n P R 2 , against a range of tumor cells, with the highest activity observed when R = phenyl, n = 2, 3 or the analogous Ph 2 PCH=CHPPh 2 (dppey) ligand , , . In recent years, an increasing number of gold(I)‐phosphine complexes have shown to display potent anti‐cancer activities , . However, the reports on cytotoxic properties of gold(I) complexes containing mixed P,N type ligands are limited , .…”