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

A series of cvclometalated gold(III) compounds [Au-m-(C boolean AND N boolean AND C)(m)L](n+) (m=1-3; n=0-3; HC boolean AND N boolean AND CH=2,6-diphenylpyridine) was prepared by ligand substitution reaction of L with N-donor or phosphine ligands. The [Au-m(C boolean AND N boolean AND C)(m)L](n+) compounds are stable in solution in the presence of glutathione. Crystal structures of the gold(m) compounds containing bridging bi- and tridentate phosphino ligands reveal the presence of weak intramolecular pi(...)pi a stacking between the [Au(C boolean AND N boolean AND C](+) units. Results of MTT assays demonstrated that the [Au-m(C boolean AND N boolean AND C](m)L](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 mu m. ne use of [Au(C boolean AND N boolean AND C)(1-methylimidazole)](+) (2a) as a model compound revealed that the gold(m)-induced cytotoxicity occurs through an apoptotic cell-death pathway. The cell-free interaction of 2a with double-stranded DNA was also examined. Absorption titration showed that 2a binds to calf-thymus DNA (ctDNA) with a binding constant of 4.5 x 10(5) dm(3) 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 2a 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 mu M) correlates to that of the metal-free phosphine ligands (IC50=0.1-38.0 mu M). with [Au-2(C boolean AND N boolean AND C)(2)(mu-dppp)](2+) (3d) and dppp (dppp = 1,2-bis(diphenylphosphino)propane), being the most cytotoxic gold(m) 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(m) compounds into nasopharyngeal carcinoma cells (SUNEI) (1.18-3.81 ng/cell: c.f.. 3d=2.04 ng/cell), suggesting the presence of non-gold-mediated cytotoxicity. Unlike 2a, both gold-(III) compounds [Au(C boolean AND N boolean AND C)(PPh3)](+) (3a) (PPh3=triphenylphosphine) and [Au-2(CA boolean AND N boolean AND C)(2)(mu-dppp)](2+) (3d) interact only weakly with ctDNA and do not arrest the cell cycle.