OPTIMIZING Ti(IV) ANTICANCER ACTIVITY BY FINE TUNING OF LIGAND DESIGN: HIGHLY POTENT COMPLEXES OF A SINGLE POLYDENTATE PHENOLATO LIGAND

Titanium(IV) complexes based on Cp and diketonato ligands have been studied extensively as anticancer agents due to their high activity toward various cancer cells and reduced side effects; however, they have not yet been utilized in the clinic due to water instability and formation of unidentified aggregates in aquatic solutions.

We introduced the improved highly cytotoxic salan titanium(IV) complexes, which exhibit slow and defined hydrolysis to form stable oxo-bridged ligand-bound polynuclear compounds. These polynuclear hydrolysis products were inactive when administered directly, due to solubility and cellular penetration limitations. Conversion of these polynuclear compounds into nanoparticles enabled overcoming these limitations and thus such nanoformulated complexes demonstrated cytotoxicity toward human and murine cancer cells. Their activity indicates that inert compounds lacking labile ligands may act as active species, and that labile ligands are not a necessity for biological activity.

Herein we present the synthesis and characterization of rationally designed anticancer Ti(IV) complexes that lack labile ligands and bear bis- and tetrakis-phenolato hexadentate ligands. These complexes are highly potent anticancer agents and are extremely stable in aquatic solutions compared with other Ti(IV) complexes; in particular they maintain their activity after long periods of exposure to aquatic solutions and blood serum, which significantly contributes to their therapeutic potential. Their hydrolytic behaviour, anti-tumor activity in vivo and in vitro, and selectivity toward cancerous cells will be discussed, as well as preliminary mechanistic aspects.