Hydrolytically Stable and Cytotoxic [ONO N]₂Ti(IV)-Type Octahedral Complexes

A new family of titanium(IV) complexes based on [ONON] diaminobis(phenolato) ligands with Me, Br, Cl, and F ortho substitutions was synthesized and characterized. X-ray structures of three derivatives revealed homoleptic L₂Ti-type compounds that exhibit an octahedral geometry without binding of the dangling amine unit. DFT calculations demonstrated that the preference of an L₂Ti complex is not driven by solvent or ligand substitutions but rather by entropic effects. Except for the fluorinated derivative that was hydrolyzed immediately following water addition at room temperature and had the lowest biological activity of the series tested, all other complexes showed cytotoxic activity comparable to or higher than (up to 10-fold) that of cisplatin toward human ovarian A2780 and colon HT-29 cancer cell lines (IC₅₀values: 0.6-13 μM after incubation for 72 h). Activity was generally higher (up to 10-fold) toward the more sensitive ovarian line and similar for all active complexes, whereas differences were recorded toward the colon line that are attributed to bioavailability variations among the complexes analyzed. Particularly high hydrolytic stability was recorded for the brominated derivative with a t_1/2of 17 ± 1 days for ligand hydrolysis in 10% D₂O at room temperature, relative to t_1/2of 56 ± 5 and 22 ± 6 h measured for the chlorinated and methylated derivatives, respectively. Altogether this series of compounds represent a promising family of anticancer agents, with the chlorinated derivative showing the best combination of stability, cytotoxicity, and bioavailability.