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. 2010 Feb;24(1):178-83.
doi: 10.1016/j.tiv.2009.09.010. Epub 2009 Sep 20.

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

Ramón Hernández  1 , Janet Méndez, José Lamboy, Madeline Torres, Féliz R Román, Enrique Meléndez
Affiliations

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

Ramón Hernández et al. Toxicol In Vitro. 2010 Feb.

Abstract

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.

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Figures

Scheme I
Scheme I
Structure of cis-[(CH3CH2O)2(bzac)2Ti(IV)].
Scheme II
Scheme II
Structure of metallocenes dihalide.
Figure 1
Figure 1
Proposed structure for titanocene-aminoacid complexes.
Figure 2
Figure 2
Dose response curves of top: [Cp2Ti(L-cysteine)2]Cl2 (diamonds), [Cp2Ti(L-methionine)2]Cl2 (triangles) and [Cp2Ti(D-penicillamine)2]Cl2 (squares); bottom: Cp2TiCl2 (squares) and [Ti4(maltolato)8(μ-O4)] (diamonds) against Caco-2 cell line at 72 hours drug exposure, determined using cell viability assay Cell Titer-Blue.
Figure 3
Figure 3
Comparison of intracellular titanium uptake by Caco-2 cells. Cp2TiCl2 (triangles), [Cp2Ti(cysteine)2]Cl2 (squares) and [Ti4(maltolato)8(μ-O4)] (diamonds).
Figure 4
Figure 4
1H NMR binding studies of [Ti4(maltolato)8(μ-O4)] and its monomeric species with calf-thymus DNA in 25 mM Tris-d11 / 10 mM NaCl (D2O) buffer at pH 7.4 and room temperature. A) mixture of 1:1 monomer:tetramer, b) after addition of 50 μL of DNA c) after addition of 100 μL of DNA.
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