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

Carefully design your ligand! A new family of highly cytotoxic TiIV complexes demonstrates strong dependence of activity on the particular ligand employed, in which small structural modifications dramatically affect both hydrolytic behavior and biological activity (see picture). Different structure‐dependence patterns are observed for hydrolysis and cytotoxicity, which are, nonetheless, strongly related. We recently introduced a new class of bis(isopropoxo)–TiIV 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 TiIV 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 TiIV cluster formation. Carefully design your ligand! A new family of highly cytotoxic TiIV complexes demonstrates strong dependence of activity on the particular ligand employed, in which small structural modifications dramatically affect both hydrolytic behavior and biological activity (see picture). Different structure‐dependence patterns are observed f