Ti(IV) complexes were the first metallodrugs to enter antineoplastic clinical trials following cisplatin, but the two initial candidates, budotitane and titanocene dichloride, failed due to low hydrolytic stability. Subsequently, our group has reported the synthesis of Ti(IV) complexes of increased stability and high cytotoxicity, initially composed of a tetradentate diaminobis(phenolato) salen or salan ligand and two labile alkoxo ligands. Afterwards, the second generation of the complexes consisted of a single, salen-derived hexadentate ligand surrounding the metal center, and exhibited high cytotoxicity, in vitro and in vivo, and increased hydrolytic stability.
Many research efforts have been dedicated toward the understanding of the cellular mechanism of action of the complexes, but without reaching an unequivocal conclusion. Recently, several studies conducted in our group pointed to the endoplasmic reticulum as a potential target organelle of phenolato Ti(IV) complexes. One study utilized the optical properties of fluorescent salan Ti(IV) complexes as a means to track their intracellular pathway using live-cell imaging, but the complexes suffered from low hydrolytic stability and decomposed quickly in the aqueous environment, thus hindering our understanding of their final targets. We aspire to create fluorescent Ti(IV) complexes of enhanced stability in order to draw full conclusions from the above-mentioned experiments. The current approach suggests the replacement of the two labile ligands of a first-generation complex with a fluorescent catechol ligand, which will enable both the tracking of the complex in the cells and the monitoring of its subsequent decomposition process. Additionally, we employ commercial fluorescent biomarkers to track cellular processes that occur in response to Ti(IV) complexes, and initial results indicate that the formation of reactive oxygen species might be involved in the mechanism. Further experiments are required to fully unravel the cellular mechanism(s) of action of phenolato Ti(IV) compounds.