Gold-Phosphine and Gold-Carbene Complexes as Potential Mitochondrial Targeting Antitumour Agents

Mitochondria play a key role in the regulation of apoptosis (cell death) and in diseases characterised by abnormal apoptotic responses such as cancer. Mitochondrial membrane permeabilisation (MMP), regulated by the mitochondrial permeability transition pore complex, is widely accepted as being central to the process of cell death. As a result there has been considerable recent interest in targeting mitochondrial cell death pathways in the development of new chemotherapeutic agents.(1) There is potential to overcome the two overriding problems in cancer chemotherapy?the common occurrence of drug-resistant tumour cells and the lack of selectivity of cancer drugs in differentiating between tumour cells and normal tissues. Significantly, carcinoma cells have an elevated mitochondrial membrane potential relative to normal cells and lipophilic cations are concentrated within mitochondria in response to mitochondrial membrane potentials. There is potential for the selective targeting to tumour cells with compounds having optimal lipophilic-hydrophilic character. Research stemming from the early 1980?s points to two distinct classes of Au(I) phosphine antitumour agents where an antimitochondrial mode of action has been implicated: (i) neutral linear two-coordinate Au(I) complexes such as triethylphosphinegold(I) chloride and the tetraacetylthioglucose gold(I) phosphine complex, Auranofin; (ii) cationic tetrahedral bis-chelated Au(I) phosphine complexes related to [Au(dppe)2]+.(2) Recently it has been reported that Auranofin, at submicromolar concentrations, induces MMP observed as mitochondrial swelling and dissipation of membrane potential.(3, 4) Both events are completely inhibited by cyclosporin-A, the specific inhibitor of MMP. The permeability changes were shown to occur at concentrations associated with the selective inhibition of mitochondrial thioredoxin reductase.(3) Auranofin is a potent and specific inhibitor of this enzyme due to Au(I) binding to the active-site selenol group.(5) The redox state of mitochondrial thiols may be critical in the control of MMP.(3) In general, swelling is stimulated by thiol blocking or oxidising agents and is prevented by thiol reducing agents.(1) Mitochondrial thioredoxin reductase may play an import role in the redox control of the permeability of mitochondrial membranes.(3) Our interest is in investigating the antitumour potential of Au(I) phosphine compounds using a number of different approaches. In recent work we have evaluated a series of hydrophilic analogs of [Au(dppe)2]+ containing pyridylphosphine ligands which have demonstrated greater tumour selectivity than the parent compound. To investigate the possible antimitochondrial mode of action we are studying the effect of [Au(dppe)2]+ and related compounds on isolated rat liver mitochondria. To assess whether the lipophiliccationic nature of the compounds determines the antitumour activity, we have synthesized a series of novel Au(I) complexes based on heterocyclic carbene rather than phosphine ligands. The similar chemistry and structural features of the two classes of complexes allow us to assess whether the phosphine ligands are essential for the antitumour properties.