Structure-activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells

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Abstract

As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of [Ti4(maltolato)8(μ-O)4], (Cp-R)2TiCl2 and (Cp-R)CpTiCl2 (R = CO2CH3 and CO2CH2CH3), and three water-soluble titanocene-amino acid complexes—[Cp2Ti(aa)2]Cl2 (aa = l-cysteine, l-methionine, and d-penicillamine)—n the human colon adenocarcinoma cell line, HT-29. The capacity of [Ti4(maltolato)8(μ-O)4] to donate Ti(IV) to human apo-transferrin and its hydrolytic stability have been investigated and compared to the previously reported data on modified titanocenes with either hydrophilic ancillary ligands or the functionalized cyclopentadienyl ligands. Notably, the titanium-maltolato complex does not transfer Ti(VI) to human apo-transferrin at any time within the first seven days of its interaction, demonstrating the inert character of this species. Stability studies on these complexes have shown that titanocene complexes decompose at physiological pH while the [Ti4(maltolato)8(μ-O)4] complex is stable at this pH without any notable decomposition for a period of ten days. The antitumor activity of these complexes against colon cancer HT-29 cells was determined using an MTT cell viability assay at 72 and 96 h. The titanocene-amino acid and the (Cp-R)2TiCl2/(Cp-R)CpTiCl2 (R = CO2CH3) complexes were not biologically active when human transferrin was absent; they also were inactive when human transferrin was present at dose-equivalent concentrations. (Cp-R)2TiCl2 and (Cp-R)CpTiCl2 (R = CO2CH2CH3) showed cytotoxic activity in HT-29 cells comparable to that which is displayed by titanocene dichloride. The titanium-maltolato complex had higher levels of cytotoxic activity than any other titanocene complex investigated. Transferrin may be important in protecting the titanium center from hydrolysis, but this may be achieved by selecting ligands that could result in hydrolytically stable, yet active, complexes.

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