Stable and flourescent cytotoxic titanium(IV) complexes for cell imaging using confocal microscopy: Toward mechanistic evaluation

The licensing of cisplatin has initiated the study of metallodrugs for the treatment of cancer. Two titanium-based drugs, budotitane and titanocene dichloride, have reached clinical trials, but failed due to instability and formulation difficulties.^[1] Subsequently, our group has introduced a new class of anticancer Ti(IV) complexes, each based on a tetradentate diaminobis(phenolato) salan or salen ligand and two labile alkoxo ligands.^[2] These complexes exhibit cytotoxicity toward cancer cells in vitro and in vivo, and display relatively high hydrolytic stability. Later on, further stabilization was achieved by the synthesis of hexadentate derivatives of the phenolato ligands, which form complexes lacking labile ligands with the titanium ion. The complexes are highly cytotoxic and stable for weeks in water.

Although various experiments have been conducted throughout the years, the mechanism of action of the cytotoxic Ti(IV) complexes remains unclear. Previously, we reported mechanistic research of the Ti(IV) cytotoxic complexes by cell imaging.^[3] This method exploited the conjugated nature of the salen molecule, where two fluorescent salen-type ligands formed two respective fluorescent tetracoordinated Ti(IV) complexes, one cytotoxic and one inactive, enabling to track their respective intracellular targets under confocal microscopy. Whereas the inactive compound spread in vesicles in the cytoplasm, the active complex appeared in the perinuclear region. Unfortunately, both complexes decomposed quickly in the biological environment, limiting our understanding of their fate in the cell. Herein, we present alternative candidates for this analysis, Ti(IV) complexes consisting of two polydentate fluorescent ligands, making the complexes cytotoxic, fluorescent and highly stable.

References:

[1] K. D. Mjos, C. Orvig, Chem. Rev. 2014, 114, 4540–4563.

[2] Michal Shavit, Dani Peri, Cesar M. Manna, A. Jacob S. Alexander, E. Y. Tshuva, J. Am. Chem. Soc. 2007, 129, 12098–12099.

[3] A. Tzubery, N. Melamed-Book, E. Y. Tshuva, Dalt. Trans. 2018, 47, 3669–3673.