Anticancer cyclometalated [AuIIIm(C∧N∧C)mL]n+ compounds: Synthesis and cytotoxic properties

Abstract

A series of cyclometalated gold(III) compounds [Aum-(C ∧N∧C)mL]n+ (m = 1-3; n=0-3: HC∧N∧CH=2,6-diphenylpyridine) was prepared by ligand substitution reaction of L with N-donor or phosphine ligands. The [Aum(C∧N∧C)mL]n+ compounds are stable in solution in the presence of glutathione. Crystal structures of the gold(in) compounds containing bridging bi- and tridentate phosphino ligands reveal the presence of weak intramolecular JI-JT stacking between the [Au(C∧N∧C)]+ units. Results of MTT assays demonstrated that the [Aum(C∧N ∧C)mL]n+ compounds containing nontoxic N-donor auxiliary ligands (2) exert anticancer potency comparable to that of cisplatin, with IC50 values ranging from 1.5 to 84 μM. The use of [Au(C∧N∧C)(1-methylimidazole)]+ (2a) as a model compound revealed that the gold(III)-induced cytotoxicity occurs through an apoptotic cell-death pathway. The cell-free interaction of 2 a with double-stranded DNA was also examined. Absorption titration showed that 2 a binds to calfthymus DNA (ctDNA) with a binding constant of 4.5 × 10 5 dm3 mol-1 at 298 K. Evidence from gel-mobility-shift assays and viscosity measurements supports an intercalating binding mode for the 2a-DNA interaction. Cell-cycle analysis revealed that 2 a causes S-phase cell arrest after incubation for 24 and 48 hours. The cytotoxicity of 3b-g toward cancer cells (IC50-0.04-4.3 μM) correlates to that of the metal-free phosphine ligands (IC50=0.1-38.0 μM), with [Au2(C∧N∧C) 2(μ-dppp)]2+ (3d) and dppp (dppp = 1,2- bis(diphenylphosphino)propane) being the most cytotoxic gold(III) and metal-free compounds, respectively. Compound 3d shows a cytotoxicity at least ten-fold higher than the other gold(III) analogues; in vitro cellular-uptake experiments reveal similar absorptions for all the gold(III) compounds into nasopharyngeal carcinoma cells (SUNE1) (1.18-3.81 ng/cell; c.f., 3d = 2.04ng/cell), suggesting the presence of non-gold-mediated cytotoxicity. Unlike 2 a, both gold(III) compounds [Au(C∧N∧C)(PPh3)]- (3a) (PPh3 = triphenylphosphine) and [Au2(C ∧N∧C)2(μ-dpPP)]2+ (3d) interact only weakly with ctDNA and do not arrest the cell cycle. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.