As stimulated by the clinical success of cis-diamminedichloroplatinum (cisplatin), a platinum(II) complex, for the treatment of cancers, scientists have paid great attention to the development of metal-based anticancer drugs which target DNA including the cisplatin analogues and some ruthenium(II)-arene complexes [Sadler, P. J. et al. Curr. Opin. Chem. Biol. 2008, 12, 197]. However, severe side effects and the induced drug resistance are commonly encountered and thus subsequently have hampered the wider applications of these DNA binding agents. Recently, some metal complexes including gold(III)-porphyrin [Che, C.-M. et al. Chem. Commun. 2011, 47, 9554-9560, Che C.-M. et al. Chem. Commun. 2003, 1718-1719.], gold(I)-NHC [J. Berners-Price, S. J., Filipovska A. et al, J. Am. Chem. Soc. 2008, 130, 12570-12571] and gold(III) dithiocarbamate [Fregona, D. et al. J. Med. Chem. 2006, 49, 1648-1657.] complexes were found to target specific proteins or enzymes, and were capable of overcoming some of the drawbacks of the DNA binding agents by virtue of their different anticancer mechanisms. Despite that numerous previously reported gold(III) complexes like, [Au(bipy)(OH)2]+ (bipy=2,2′-bipyridine), [Messori, L. et al. Coord. Chem. Rev. 2009, 253, 1692-1707] showed satisfied antiproliferative ability, examples on in vivo tumor inhibition are sparse.
Fluorescent thiol-sensitive probes have spurred increasing interests especially in biological area, as the cellular thiol level is linked with a great many diseases like cancer, AIDS (Acquired immune deficiency syndrome) and so forth [Yoon, J., Chem. Soc. Rev. 2010, 39, 2120-2135; Herzenberg, L. A. et al. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 1967-1972]. Soft metals and metals with tunable redox potentials should be a good starting point to design thiol probes. Gold(III) complexes are always unstable under physiological conditions and will be reduced to Au(I) or even Au(0) by physiological thiols. As Au(III) is usually 4-coordinated but Au(I) is usually 2-coordinated, reduction of Au(III) to Au(I) is accompanied by the release of coordinated ligand(s). If the ligand is highly fluorescent, intraligand emission would be quenched due to the presence of low energy Au(III) 5dx2-y2 orbital. Upon reduction of Au(III) to Au(I) by thiols, the fluorescent ligand(s) will be released and switch on the emission.
While the anti-cancer properties of many gold complexes including that of Au(III) and Au(I) are attributed to Au(I), Au(I) ion is unstable under physiological conditions [Sadler, P. J. et al. Met.-Based Drugs 1994, 1, 107-144]. The present inventors discovered that N-heterocyclic carbene (NHC) ligand(s) is able to stabilize Au(I) against reduction to Au(0) and/or demetalation under physiological conditions.
As 2,6-bis(1H-benzo[d]imidazol-2-yl)pyridine (H2BPB) and its analogue 2,6-di(1H-imidazol-2-yl)pyridine (H2IPI) and 2,6-di(1H-pyrazol-5-yl)pyridine (H2PPP) are highly emissive and also widely used in biological systems [Che, C.-M. et al. Chem. Eur. J. 2010, 16, 6900-6911], the present inventors employ the scaffold to develop novel gold(III) complexes.
Thus, the gold(III) complexes containing multi-dentate N^N^N ligand and NHC moiety provide dual anti-cancer and fluorescent switch-on properties.