Cytotoxic titanium(IV) complexes of chiral diaminobis(phenolato) ligands: Better combination of activity and stability by the bipyrrolidine moiety

Racemic and enantiomerically pure titanium(IV) complexes with ortho-bromo-para-methyl-substituted diaminobis(phenolato) ligands were prepared with NH-, NMe-, and bipyrrolidine-based diamino bridges through ligand-to-metal chiral induction. The hydrolytic stability of the complexes was evaluated, and their cytotoxicity was measured using HT-29 human colon cancer cells based on the MTT assay. All stereochemical forms of the NMe-based complexes, although demonstrating the highest hydrolytic stability, were biologically inactive. For the NH and bipyrrolidine-based active complexes, the pure enantiomers exhibited high cytotoxicity whereas the racemic mixtures were inactive, supporting the involvement of a polynuclear active species. The bipyrrolidine complexes appear to provide the best combination of hydrolytic stability and biological activity, presumably by minimizing steric bulk and consequently enabling biological accessibility. Racemic and optically pure phenolato titanium(IV) complexes were prepared with NH, NMe, and bipyrrolidine-based diamino bridges. The optically pure bipyrrolidine complexes provide the best combination of hydrolytic stability and biological activity, presumably by maintaining small enough steric bulk to enable biological accessibility.