Cytotoxic Titanium Salan Complexes: Surprising Interaction of Salan and Alkoxy Ligands

Abstract

The synthesis, biochemical evaluation, and hydrolysis studies of a wide selection of alkyl- and halogen-substituted titanium salan alkoxides are presented herein. A systematic change in the employed alkoxides revealed that both the bulk of the salan ligands and the steric demand of the labile ligands are of great importance for the obtained biological activity. Surprisingly, these two factors are not independent from each other; lowering the steric demand of the alkoxide of a hitherto nontoxic complex renders it cytotoxic. Therefore, our data suggest that the overall size of the complex exerts a strong influence on its biological activity. To decide whether the correlation between the cytotoxicity and the steric demand of the whole complex is merely based on an altered hydrolysis or on the interaction with biomolecules, the behavior of selected complexes under hydrolytic conditions and the influence of transferrin were investigated. Complexes differing only in their labile alkoxy ligands gave the same hydrolysis products with similar hydrolysis rates but displayed cytotoxicities that differed in the range of one order of magnitude. Thus, it seems that the hydrolysis product is not the active species but rather that the unhydrolysed complex is important for the first interaction with a biomolecule. This promoted the idea of hydrolysis being a detoxification pathway. In accordance with the above conclusion, chloro-substituted complex [Ti(Ph(Cl)N(Me))(2)(O(iPr))(2)] displayed a high cytotoxicity (IC(50) approximately 5 microM) and surprisingly high hydrolytic stability (t(1/2)=108 h). These findings, together with the observed cytotoxicity in a cisplatin-resistant cell line, make halo-substituted salan complexes an interesting target for further studies.

Cytotoxicity of a Ti(IV) compound is independent of serum proteins

“…HBED is a cell-permeable molecule that is a promising candidate for iron-overload disease therapy because of its high Fe(III) affinity (41). Ti(IV) compounds of diamine-bis(phenolato) ligands, which are related to HBED but lack the carboxylate appendages, display cytotoxic properties in different cell lines in vitro (14,17,19,28,(42)(43)(44) and in a mouse cancer model in vivo (35). It is feasible that Ti(IV) compounds of citrate and HBED could use ligand-specific mechanisms for transport into cells.…”

“…In one study, structurally similar titanocenes that deliver Ti(IV) to Tf at comparably fast rates and degrees of saturation were found not only to poorly induce cytotoxicity in HT-29 colon cancer cells but also to induce at different half-maximal inhibitory concentrations (IC 50 ) (15). In more conclusive studies, the addition of Tf to cell-viability assays did not improve the cytotoxicity of different Ti(IV) compounds in several cell lines, with the exception of titanocene dichloride in some instances (16)(17)(18)(19).…”

Heptacoordinate Heteroleptic Salan (ONNO) and Thiosalan (OSSO) Titanium(IV) Complexes: Investigation of Stability and Cytotoxicity

“…45 These diamine bis-phenolatebound titanium (IV) alkoxides hydrolyze in the course of hours to days in NMR experiments with their limited amount of water. 15,22 This now arouses the question, why do other "stable" complexes show appreciable bioactivity whereas [L 4 Ti(dipic) 1 ] does not? In [L 4 Ti(dipic) 1 ], the titanium(IV) center is closely surrounded by the dipic and the bulky tert-butyl substituted salan (c.f.…”

A ubiquitous metal, difficult to track: towards an understanding of the regulation of titanium(iv) in humans

“…However, numerous studies have shown that sTf may not be as important as thought in facilitating Ti(IV) cytotoxicity. 67–71 Even at 100 μM concentration Ti 2 Tf does not exhibit any cytotoxic behavior against A549 and MRC (normal) human lung cell lines. 3, 33 …”