Cytotoxic titanium(IV) complexes: Renaissance

In this paper we overview our studies on amine-phenolato Ti^IV complexes as cytotoxic agents, in the context of the results reported thus far with titanocene dichloride, budotitane and derivatives. In particular, we emphasize the studies about the structure-activity relationship performed and important insights gained with the known compounds and our complexes, in regards to their hydrolytic behavior and cyto- toxic activity, while pointing to potential mechanistic aspects. Titanocene dichloride and budotitane show cytotoxic activity towards cells that are resistant to cisplatin with reduced side effects. Their main drawback is their hydrolytic instability that has impeded mechanistic investigations and pharmaceutical use. Our new family of cytotoxic complexes was designed to include a single highly electron-donating chelating ligand to afford octahedral Ti^IV complexes of relatively high hydrolytic stability, with the aim to retain ligand binding throughout the biological activity for achieving controlled processes and allowing mechanistic evaluation. The effect of several parameters on hydrolysis and cytotoxicity were investigated, including those relating to the tetradentate ligand and those relating to the labile groups. Overall we observed high cytotoxic activity that is strongly dependent on the li- gand, and which is strongly correlated to the complex hydro- lytic behavior. Additional mechanistic studies provide insights regarding the time frame of activity and cell penetration. Some comparisons to titanocene dichloride, budotitane and analogues are highlighted.