Invited
Anticancer titans: Potent, resilient, and safe phenolato Ti(IV) antitumor agents

Titanium(IV) complexes are promising alternatives to platinum-based anticancer chemotherapy, based not only on their wider activity range with no reports on Ti resistance, but mainly on the biocompatibility of the Ti(IV) metal. Although early Ti(IV) compounds such as titanocene dichloride and budotitane failed clinical trials over thirty years ago due to hydrolytic instability and formulation difficulties, later compounds pheolato- based that we have introduced in the past decade demonstrate enhanced hydrolytic stability and resilience in water solutions. The final hydrolysis of these compounds to the safe thermodynamic product titanium dioxide, which is often present in food and drugs with no known side effects, remains an enormous advantage for the use of Ti(IV) complexes as tolerable non-toxic drugs.

Herein an advanced family of titanium(IV) phenolato compounds will be presented, demonstrating a combination of high potency in vitro and in vivo ‒ alone and in combinations, a wide activity range as established on the NCI-60 panel, no signs of toxicity in vitro (toward non-cancerous cells) and in vivo (to treated mice), and particularly high resistance to hydrolysis in various biological solutions including cell media and sera. Preliminary findings on the distinct mode of action of these compounds will also be discussed.

This project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreements 681243, 779689)

[1] M. Shavit, D. Peri, C. M. Manna, J. S. Alexander, E. Y. Tshuva, J. Am. Chem. Soc. 2007, 129, 12098.

[2] S. Meker, K. Margulis-Goshen, E. Weiss, S. Magdassi, E. Y. Tshuva, Angew. Chem. Int. Ed. 2012, 51, 10515.

[3] S. Meker, O. Braitbard, M. D. Hall, J. Hochman, E. Y. Tshuva Chem. Eur. J. 2016, 22, 9986.

[4] N. Ganot, O. Braitbard, A. Gammal, J. Tam, J. Hochman, E. Y. Tshuva ChemMedChem. 2018, 13, 2290.