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 Cp(2)TiCl(2) and three water soluble titanocene-amino acid complexes - [Cp(2)Ti(aa)(2)]Cl(2) (aa=L-cysteine, L-methionine, and D-penicillamine) and one water soluble coordination compound, [Ti(4)(maltolato)(8)(micro-O)(4)] on the human colon adenocarcinoma cell line, Caco-2. At pH of 7.4 all titanocene species decompose extensively while [Ti(4)(maltolato)(8)(micro-O)(4)] is stable for over seven days. In terms of cytotoxicity, the [Cp(2)Ti(aa)(2)]Cl(2) and [Ti(4)(maltolato)(8)(micro-O)(4)] complexes exhibited slightly higher toxicity than titanocene dichloride at 24h, but at 72h titanocene dichloride and [Ti(4)(maltolato)(8)(micro-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.

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

As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of [Ti(4)(maltolato)(8)(mu-O)(4)], (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(3) and CO(2)CH(2)CH(3)), and three water-soluble titanocene-amino acid complexes-[Cp(2)Ti(aa)(2)]Cl(2) (aa = L: -cysteine, L: -methionine, and D: -penicillamine)-on the human colon adenocarcinoma cell line, HT-29. The capacity of [Ti(4)(maltolato)(8)(mu-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 [Ti(4)(maltolato)(8)(mu-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)(2)TiCl(2)/(Cp-R)CpTiCl(2) (R = CO(2)CH(3)) 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)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(2)CH(3)) 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.

Synthesis, Solution and Solid State Structure of Titanium-Maltol Complex.

The reaction of Cp(2)TiCl(2) with two equivalents of maltol (3-hydroxy-2-methyl-4-pyrone) in water, at room temperature and pH of 5.4, leads to a complete replacement of Cp and chloride ligands affording, Ti(maltolato)(2)(OH)(2.) The complex has been characterized by IR, NMR and ESI-MS spectroscopic and cyclic voltammetry methods. In DMSO-d(6) solution, the complex shows two isomers in a ratio of 4:1, in which one OH signal can be identified per isomer. This suggests that in solution the complex is monomeric, most likely a chiral cis-Ti(maltolato)(2)(OH)(2) and trans-Ti(maltolato)(2)(OH)(2). The monomeric nature of the complex (in water/methanol 1:1) was verified by ESI-MS spectroscopy, showing a parent peak at 329 m/z. Electrochemical behavior of Ti(maltolato)(2)(OH)(2) using cyclic voltammetry experiments showed the complex undergoes irreversible reduction in aprotic solvents. In D(2)O solution, at pH of 8.4, the (1)H NMR spectrum of the complex shows a mixture of monomer and tetramer Ti(IV)-maltol complexes in a ratio of 1:1. The crystallization of Ti(maltolato)(2)(OH)(2) at pH of 8.4 leads to the formation of [Ti(4)(maltolato)(8)(µ-O(4))]•18H(2)O. A single crystal of [Ti(4)(maltolato)(8)(µ-O(4))]•18H(2)O was analyzed by X-ray diffraction methods. The complex crystallizes in a monoclinic space group P2(1)/c with a = 12.617(4) Å, b = 24.058(8) Å, c = 22.686(7) Å, ß= 97.678(4)° and V = 6824(4) Å(3) for Z = 4. Solid state structure determination of the Ti-maltol complex showed to be tetrameric, containing two bridging oxides (in cis position) and two bidentate maltol ligands per titanium in a pseudo-octahedral coordination geometry.