Synthesis, Characterization, Cytotoxicity, and Hydrolytic Behavior of C₂‐ and C₁‐Symmetrical Ti^IV Complexes of Tetradentate Diamine Bis(Phenolato) Ligands: A New Class of Antitumor Agents

Abstract

We recently introduced a new class of bis(isopropoxo)-Ti(IV) complexes with diamine bis(phenolato) ligands that possess antitumor activity against colon HT-29 and ovarian OVCAR-1 cells that is higher than that of the known Ti(IV) compounds titanocene dichloride and budotitane as well as that of cisplatin. Herein, we elaborate on this family of compounds; we discuss the effect of structural parameters on the cytotoxic activity and hydrolytic behavior of these complexes, seeking a relationship between the two. Whereas complexes with small steric groups around the metal center possess high activity and lead mostly to formation of O-bridged polynuclear complexes with bound bis(phenolato) ligand upon water addition, bulky complexes hydrolyze to release all free ligands and are inactive. Slightly increasing the size of the N-donor substituents probably weakens the ligand binding in solution, and, thus, rapid hydrolysis is observed, leading to a lack of cytotoxicity, supporting the requirement for ligand inertness. Replacing the two isopropoxo ligands with a single catecholato unit gives a complex with a different geometry that exhibits slower hydrolysis and reduced cytotoxicity, suggesting some participation of labile ligand hydrolysis in the cytotoxicity mechanism. A crystallographically characterized O-bridged polynuclear species obtained from a biologically active bis(isopropoxo) complex upon water addition is inactive, which rules out its participation as the active species, yet suggests some role of the particular steric and electronic requirements allowing its formation in the activity mechanism. Additional measurements support rapid formation of the active species in the presence of cells prior to O-bridged Ti(IV) cluster formation.

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

“…Recent studies by Tshuva and co-workers that utilized catechol as a bidentate substitute for the isopropoxy groups showed a two-fold decrease in the cytotoxicity of the resulting complex. [40] Although the observed effect is significant, an explanation is not evident because not only is the steric influence altered, but also the exchange of the two monodentate isopropoxy groups for one bidentate catecholato ligand leads to a different complex geometry. In the starting complex the isopropoxy groups are oriented in a cis fashion, but the two phenolato substituents of the salan are now occupying their position, which results in a loss of symmetry.…”

“…For alkyl-substituted salans, it has already been shown that the cell penetration mechanism is independent of transferrin. [40] Remarkably, even though the mechanism of action seems to be different for halogen-sub- 2 ]complexes by using the AlamarBlue assay with Hela S3 and Hep G2 cells. The cells were incubated with the complexes for 48 h prior measurement.…”

“…[39] By using a small collection of six alkyl-substituted titanium salan complexes, Tshuva and co-workers showed an influence due to the steric demand of the ligand and proposed a connection between the hydrolytic behavior of these complexes and their biological activity. [40][41][42] Exploring this third class of titanium complexes with antitumor activity, we could demonstrate that complexes of halogen-substituted salans in particular reveal promising biological properties. Their IC 50 values are comparable to cisplatin and, in contrast to their alkyl-substituted congeners, they almost exclusively induce apoptotic cell death.…”

“…[40] Therefore, we were interested in restoring the cytotoxicity of similar complexes just by lessening the steric demand of the alkoxide groups.…”

Bringing Radiotracing to Titanium-Based Antineoplastics: Solid Phase Radiosynthesis, PET and ex Vivo Evaluation of Antitumor Agent [45Ti](salan)Ti(dipic)

“…However, recent advances in titanium-stabilizing ligands have led to a new class of cytotoxic Ti-based antineoplastics 5 . Prominently, introduction of the ligand salan, a diamine bisphenalato compound, conferred excellent hydrolytic stability to Ti(IV) alkoxide complexes, as presented by Tshuva and co-workers (Chart 1, 1) [6][7][8][9][10][11][12][13] . Many of these compounds also demonstrated micro-and submicromolar antiproliferative activity against HT29 and OVCAR-1 cancer cell lines in vitro.…”