Triethylphosphine gold iodide (I), the iodido analogue of Auranofin: comparative studies of a potential antineoplastic agent

Auranofin [2,3,4,6-tetra-o-acetyl-L-thio-β-D-glycopyranosato-S-(triethyl- phosphine)-gold(I)] (AF) is an important oral chrysotherapeutic agent of established clinical efficacy in the treatment of rheumatoid arthritis. In the last few years, this drug has attracted growing attention for its important pharmacological properties as a prospective anticancer and antibacterial agent according to innovative drug repurposing strategies. Selective chemical modification of auranofin might lead to a modulation and hopefully an improvement of its pharmacological profiles. Accordingly, we decided to prepare an AF derivative where the thiosugar ligand is replaced by iodide i.e. triethylphosphine gold iodide (I). Replacement of the thiosugar ligand with iodide should afford a compound of increased lipophilicity thus favoring bioavailability. The novel compound was investigated in depth for its chemical and biological properties in comparison to AF and to its chlorido analogue. Solution behavior was assessed by 31P NMR spectroscopy and the crystal structure solved. To better characterise the molecular aspects of the interaction of these drugs with biological targets, we studied their reactivity toward the model protein lysozyme, a GG rich oligonucleotide, and ds ctDNA, through ESI-MS and ethidium bromide assay. Upon replacing the thiosugar with different halides i.e. chloride and iodide, we assisted to complete inhibition of reactivity toward proteins, at variance with AF that interacts with HEWL through the formation of non-covalent adduct. Replacement of thiosugar with halide ligands, instead, does not inhibit the reactivity toward DNA models. Antiproliferative properties of I were comparatively determined on HCT8 and HCT116 cells, two representative cell lines of colorectal cancer (CRC), highlighting the potent cytotoxic effect of these compounds on CRC cell lines, with an IC50 value falling in the nM range. Furthermore, cell cycle and apoptosis experiments were carried out to investigate whether the structural modification made on AF imply differences in the mechanisms through which apoptosis and cell cycle arrest are triggered. Overall, we believe that this novel analogue of AF manifests a number of chemical and biological features that render it particularly interesting and suitable for further preclinical testing in appropriate in vivo models of CRC.