Exceptionally Stable Anticancer Titanium(IV) Complexes Baring Hexadentate Phenolato Ligands

Sigalit Meker, The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel
Edit Y. Tshuva, The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel

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 low side effects; however, they have not yet been utilized in the clinic due to water instability and formation of unidentified aggregates in aquatic solutions. Therefore, mechanistic aspects remain unresolved, including the nature of the active species and its identification out of the multiple hydrolysis products formed.

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, thus enabling mechanistic evaluation. The 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.

Herein we present the synthesis and characterization of rationally designed anticancer Ti(IV) complexes that lack labile ligands and bare bis- and tetrakis-phenolato hexadentate ligands. These complexes are highly cytotoxic 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, thus significantly contributing to their therapeutic potential. Their hydrolytic behaviour, cytotoxicity, and selectivity toward cancerous cells will be discussed, as well as mechanistic aspects such as bioavailability, cellular distribution, potential biological targets, and the identity of intracellular active species.

1. Meker S., Tshuva E. Y., in preparation.

2. Meker S., Margulis-Goshen K., Weiss E., Braitbard O., Hochman J., Magdassi S., Tshuva E. Y., ChemMedChem 9, 1294, 2014.

3. Meker S., Margulis-Goshen K., Weiss E., Magdassi S., Tshuva E. Y., Angew. Chem. Int. Ed. 51, 10515, 2012; selected for back cover.