Antitumor reactivity of non-metallocene titanium complexes of oxygen-based ligands: is ligand lability essential?

In our attempt to define the parameters affecting anticancer activity of titanium complexes and to assess the role of hydrolytic stability, titanium compounds of oxygen-based ligands were studied. A homoleptic complex of hydroxyamino-1,3,5-triazine ligands was prepared and its hydrolysis was investigated by UV-vis spectroscopy at biologically relevant pH and temperature conditions based on its ligand to metal charge transfer absorption band. This complex exhibits very high hydrolytic stability under the conditions measured with negligible ligand dissociation. Its anticancer reactivity was investigated on ovarian OVCAR-1 and colon HT-29 cells, in comparison with the reference highly labile Ti(OiPr)(4) and TiCl(4)(THF)(2) (where THF is tetrahydrofuran), the inert thermodynamically stable TiO2, and the free aromatic hydroxyamino-1,3,5-triazine ligand. Whereas all reference titanium complexes were found to be completely unreactive against both tumor cell types, suggesting some moderate inertness is required, the homoleptic complex of the triazine ligands clearly possess some mild reactivity despite having no labile groups, and despite its incomplete solubility in the concentrations applied. As the free aromatic ligand is highly active under similar conditions, detailed time-dependence measurements were conducted and indicated that the cytotoxicity of the ligand is more affected by reducing incubation time, and that introducing the titanium complex to the medium prior to cell administration does not increase reactivity at a certain incubation time. These findings suggest that the reactivity of the complex does not result from that of the free ligand following dissociation, but rather involves the titanium center.