Titanium(IV) complexes: Cytotoxicity and cellular uptake of titanium(IV) complexes on caco-2 cell line

Replacement of the ancillary ligand in titanocene dichloride by amino acids provides titanocene species with high water solubility. As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of Cp2TiCl2 and three water soluble titanocene-amino acid complexes – [Cp2Ti(aa)2]Cl2 (aa = l-cysteine, l-methionine, and d-penicillamine) and one water soluble coordination compound, [Ti4(maltolato)8(μ-O)4] on the human colon adenocarcinoma cell line, Caco-2. At pH of 7.4 all titanocene species decompose extensively while [Ti4(maltolato)8(μ-O)4] is stable for over seven days. In terms of cytotoxicity, the [Cp2Ti(aa)2]Cl2 and [Ti4(maltolato)8(μ-O)4] complexes exhibited slightly higher toxicity than titanocene dichloride at 24 h, but at 72 h titanocene dichloride and [Ti4(maltolato)8(μ-O)4] have higher cytotoxic activity. Cellular titanium uptake was quantified at various time intervals to investigate the possible relationship between Ti uptake and cellular toxicity. Results indicated that there was not a clear relationship between Ti uptake and cytotoxicity. A structure–activity relationship is discussed.