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Anticancer Cyclometalated [Au III m (C ∧ N ∧ C) m L] n + Compounds: Synthesis and Cytotoxic Properties
Author(s) -
Li Carrie KaLei,
Sun Raymond WaiYin,
Kui Steven ChiFai,
Zhu Nianyong,
Che ChiMing
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200600117
Subject(s) - chemistry , stereochemistry , cytotoxicity , adduct , ligand (biochemistry) , crystallography , medicinal chemistry , in vitro , organic chemistry , receptor , biochemistry
A series of cyclometalated gold( III ) compounds [Au m (C ∧ N ∧ C) m L] 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 [Au m (C ∧ N ∧ C) m L] 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 π⋅⋅⋅π stacking between the [Au(C ∧ N ∧ C)] + units. Results of MTT assays demonstrated that the [Au m (C ∧ N ∧ C) m L] n + compounds containing nontoxic N‐donor auxiliary ligands ( 2 ) exert anticancer potency comparable to that of cisplatin, with IC 50 values ranging from 1.5 to 84 μ M . The use of [Au(C ∧ N ∧ 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 4.5×10 5 dm 3 mol −1 at 298 K. Evidence from gel‐mobility‐shift assays and viscosity measurements supports an intercalating binding mode for the 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 (IC 50 =0.04–4.3 μ M ) correlates to that of the metal‐free phosphine ligands (IC 50 =0.1–38.0 μ M ), with [Au 2 (C ∧ N ∧ C) 2 (μ‐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 ∧ N ∧ C)(PPh 3 )] + ( 3 a ) (PPh 3 =triphenylphosphine) and [Au 2 (C ∧ N ∧ C) 2 (μ‐dppp)] 2+ ( 3 d ) interact only weakly with ctDNA and do not arrest the cell cycle.