ABSTRACT
A library of new bis-picolinamide ruthenium(III) dihalide complexes of the type [RuX2 L2 ] (X=Cl or I, L=picolinamide) have been synthesised and characterised. The complexes exhibit different picolinamide ligand binding modes, whereby one ligand is bound (N,N) and the other bound (N,O). Structural studies revealed a mixture of cis and trans isomers for the [RuCl2 L2 ] complexes but upon a halide exchange reaction to yield [RuI2 L2 ], only single trans isomers were detected. High cytotoxic activity against human cancer cell lines was observed, with the potencies of some complexes similar to or better than cisplatin. The conversion to [RuI2 L2 ] substantially increased the activity towards cancer cell lines by more than twelvefold. The [RuI2 L2 ] complexes displayed potent activity against the A2780cis (cisplatin-resistant human ovarian cancer) cell line, with a more than fourfold higher potency than cisplatin. Equitoxic activity was observed against normoxic and hypoxic cancer cells, which indicates the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency. The activity of selected complexes against non-cancer ARPE-19 cells was also tested. The [RuI2 L2 ] complexes were found to be more potent than the [RuCl2 L2 ] analogues and also more selective towards cancer cells with a selectivity factor in excess of sevenfold.
Subject(s)
Antineoplastic Agents/chemistry , Chlorides/chemistry , Coordination Complexes/chemistry , Iodides/chemistry , Ruthenium/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Cell Hypoxia , Cell Line , Cell Survival/drug effects , Cisplatin/toxicity , Coordination Complexes/chemical synthesis , Coordination Complexes/toxicity , Crystallography, X-Ray , Drug Resistance, Neoplasm/drug effects , Humans , Isomerism , Ligands , Molecular ConformationABSTRACT
Group IV metal complexes have previously shown promise as novel anticancer agents. Here, we discuss the mechanistic and cytotoxic nature of a series of group IV ß-diketonate coordination complexes. Clear evidence that the ligands are exchangeable on the metal centre and that the ß-diketonate ligands can act as potential drug delivery vehicles of the group IV metal ions was obtained. When evaluated for the cytotoxicity against human colon adenocarcinoma (HT-29) and human breast adenocarcinoma (MCF-7) cell lines, a general trend of decreasing potency down the group IV metals was observed. The most promising results obtained were for the hafnium complexes, with the tris diphenyl ß-diketonate hafnium complex exhibiting IC50 values of 4.9 ± 0.9 µM and 3.2 ± 0.3 µM against HT-29 and MCF-7, respectively, which are comparable with the activity of cisplatin against the same cell lines. This tri ß-diketonate hafnium complex is the first to show potent in vitro cytotoxic activity. The results reported show that ligand design has a significant effect on the cytotoxic potential of the complexes, and that these group IV complexes warrant further evaluation as novel metal-containing anticancer agents.
