Anticancer cyclometalated [Au(III)m(C(wedge)N(wedge)C)mL]n+ compounds: Synthesis and cytotoxic properties.
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.
Li
Carrie Ka-Lei
CK
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Sun
Raymond Wai-Yin
RW
Kui
Steven Chi-Fai
SC
Zhu
Nianyong
N
Che
Chi-Ming
CM
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D010720:Phosphines / Q000138:chemical synthesis / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet; D019098:Telomerase / Q000037:antagonists & inhibitors; D014783:Viscosity
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007364:Intercalating Agents; D008024:Ligands; D050607:Organogold Compounds; D010720:Phosphines; D004247:DNA; D019098:Telomerase