Cytotoxic Titanium(IV) Complexes of Salalen-Based Ligands

A new family of cytotoxic Ti^IV complexes is described, based on the salalen (half salan and half salen) ligands. Altogether, 17 (salalen)Ti^IV complexes with different ligand substitutions and different numbers of labile groups were synthesized. Representative complexes were characterized by X-ray crystallography. The complexes were evaluated for their hydrolytic stability in 10 % D₂O solutions, their cytotoxicity toward HT-29 human colon cancer cells, and the retaining of activity after pre-incubation in aquatic medium prior to cell addition. The results showed that: (a) reducing complexes' lability increased hydrolytic stability, (b) bulky groups often increased kinetic stability toward hydrolysis, but also damaged accessibility, (c) for unstable complexes, some hydrolysis products are likely the active species, (d) specific hydrophobic groups may facilitate penetration through the cell membrane, and (e) one di-tert-butylated salalen catecholato complex was identified as the superior derivative, combing high cytotoxicity with high stability and accessibility.