Anticancer Cyclometalated [Au^III_m(C^∧N^∧C)_mL]ⁿ⁺ Compounds: Synthesis and Cytotoxic Properties

Abstract

A series of cyclometalated gold(III) compounds [Au(m)(C(wedge)N(wedge)C)mL]n+ (m = 1-3; n = 0-3; HC(wedge)N(wedge)CH = 2,6-diphenylpyridine) was prepared by ligand substitution reaction of L with N-donor or phosphine ligands. The [Au(m)(C(wedge)N(wedge)C)mL]n+ compounds are stable in solution in the presence of glutathione. Crystal structures of the gold(III) compounds containing bridging bi- and tridentate phosphino ligands reveal the presence of weak intramolecular pi pi stacking between the [Au(C(wedge)N(wedge)C)]+ units. Results of MTT assays demonstrated that the [Au(m)(C(wedge)N(wedge)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 microM. The use of [Au(C(wedge)N(wedge)C)(1-methylimidazole)]+ (2 a) 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 calf-thymus DNA (ctDNA) with a binding constant of 4.5 x 10(5) dm3 mol(-1) at 298 K. Evidence from gel-mobility-shift assays and viscosity measurements supports an intercalating binding mode for the 2 a-DNA interaction. Cell-cycle analysis revealed that 2 a causes S-phase cell arrest after incubation for 24 and 48 hours. The cytotoxicity of 3 b-g toward cancer cells (IC50 = 0.04-4.3 microM) correlates to that of the metal-free phosphine ligands (IC50 = 0.1-38.0 microM), with [Au2(C(wedge)N(wedge)C)2(mu-dppp)]2+ (3 d) and dppp (dppp = 1,2-bis(diphenylphosphino)propane) being the most cytotoxic gold(III) and metal-free compounds, respectively. Compound 3 d 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., 3 d = 2.04 ng/cell), suggesting the presence of non-gold-mediated cytotoxicity. Unlike 2 a, both gold(III) compounds [Au(C(wedge)N(wedge)C)(PPh3)]+ (3 a) (PPh3 = triphenylphosphine) and [Au2(C(wedge)N(wedge)C)2(mu-dppp)]2+ (3 d) interact only weakly with ctDNA and do not arrest the cell cycle.

Stable Anticancer Gold(III)–Porphyrin Complexes: Effects of Porphyrin Structure

“…[5] However, most of these cytotoxic goldA C H T U N G T R E N N U N G (III) complexes are susceptible to spontaneous reduction to gold(I) and colloidal gold under physiological conditions. [5,6] In the literature, there are only a few cytotoxic goldA C H T U N G T R E N N U N G (III) complexes, including [Au III A C H T U N G T R E N N U N G (bipy c -H)(OH)]A C H T U N G T R E N N U N G [PF 6 ] (bipy c -H = deprotonated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine), [6u] [Au III -A C H T U N G T R E N N U N G (dmamp)Cl 2 ] (dmamp = 2-(dimethylaminomethyl)phenyl), [7] [Au III m A C H T U N G T R E N N U N G (C^N^C) m L] n + (m = 1-3; n = 0-3; HC^N^CH = 2,6-diphenylpyridine), [8] and the [AuA C H T U N G T R E N N U N G (Por)] + complexes (Por = porphyrinato ligand) [9] that are known to exhibit significant anticancer activity, as well as excellent solution stability.…”

Light-induced catalytic and cytotoxic properties of phosphorescent transition metal compounds with a d 8 electronic configuration

“…Some of these compounds were found to display promising in vitro and in vivo anti-cancer activities. The two representative classes of gold(III) compounds are the ones with porphyrin ligands and those with doubly deprotonated C ∧ N ∧ C ligands (where HC ∧ N ∧ CH = 2,6-diphenylpyridine) [41][42][43].…”

(μ-Diphenylphosphanido-κ2 P:P′)bis[2,2′-(pyridine-2,6-diyl)diphenyl-κ3 C 1,N,C 1′)gold(III)] perchlorate acetonitrile solvate

“…The stability of metal compounds is usually enhanced by multidentate chelating ligands. Li and his co-workers have reported multinuclear gold complex of 2,6-diphenyl-Pyridine ligand (dpp) to generate a planar gold(III) moiety (Li et al, 2006). In this context, the title complex, (I), has been prepared and its crystal structure is reported here.…”

“…Each Au atom is surrounded by one P atom from diphenylphosphanide ligand and two C atoms, one N atom from dpp in a square-planar geometry, the least-squares plane through Au III and dpp has a mean deviation of 0.04 (3) Å. The intramolecular Au···Au contact of 3.788Å is beyond a normal range of metal-metal interactions for d 8 metal ions (3.09-3.50 Å) (Yam et al, 2002;Goshe et al, 2003;Lu et al, 2004 (Li et al, 2006). The interplanar separation between two neighbouring dpp molecules are 3.40 and 3.57Å (Fig.…”

“…For related literature, see: Goshe et al (2003); Kui et al (2006); Li et al (2006); Lu et al (2004); Wong et al (1998); Yam et al (2002).…”