PHENOLATO TITANIUM(IV) COMPLEXES: STABLE AND ABLE ANTICANCER AGENTS

Titanium(IV) is a promising metal for anticancer chemotherapy, as an alternative for platinum. A main advantage of the titanium metal is its biocompatibility; titanium oxide, the final hydrolysis product of titanium(IV) complexes in biological environment, is an inert safe material with no known side effects or any dietary restrictions, which is often present in food and cosmetic products. Titanium(IV) based compounds that previously reached clinical trials showed wider activity range and reduced toxicity relative to cisplatin, but readily hydrolyzed in biological solutions, inhibiting mechanistic analysis and medicinal development.

We have introduced the phenolato titanium(IV) complexes as superior anti-tumor agents.^[1-3] Such complexes showed activity higher than that of cisplatin toward numerous human cancer cell lines, including cells resistant to known drugs, with marked cancer selectivity. Importantly, enhanced hydrolytic stability was recorded for various derivatives; in fact, leading compounds showed no decomposition for weeks in water, while maintaining high anti-cancer activity both in vitro and in vivo.

Herein, the tale on the design and developmental stages for several generations of compounds will be overviewed, along with the insights gained throughout, directing the research paths to the current state of knowledge. Structure-activity relationships will be presented, along with mechanistic insights on the compounds activity in the cell, including the nature of the active species and possible cellular targets.

Selected References

[1] M. Shavit, D. Peri, C. M. Manna, J. S. Alexander, E. Y. Tshuva, J. Am. Chem. Soc. 2007, 129, 12098-9.

[2] C. M. Manna, O. Braitbard, E. Weiss, E. Y. Tshuva, Chem. Med. Chem. 2012, 7, 703-8.

[3] S. Meker, K. Margulis-Goshen, E. Weiss, S. Magdassi, E. Y. Tshuva, Angew. Chem. Int. Ed. 2012, 51, 10515-7.