The biological targets of antitumor titanium(IV) complexes: Celluar detection of fluorinated compounds

Ti(IV) complexes serve as a leading alternative for cisplatin-based chemotherapy. Our group introduced bis(phenolato)bis(alkoxo) Ti(IV) complexes that exhibit marked cytotoxicity in vitro and in vivo. Moreover, these complexes demonstrate high cytotoxic activity toward cisplatin-resistant cancer cell lines, which imply on different mechanism of action from that of cisplatin. These results raised the importance in gaining mechanistic insights on the antitumor activity of the titanium(IV) complexes. Detection of the active species in the cells, revealing their cellular pathway, and discovering the biological targets, constitute essential milestones toward the complete understanding of the Ti(IV) anticancer mechanism.

The broad variety of biomolecules and the complex processes in the cell challenge the cellular detection of a single compound. Therefore, we utilized ¹⁹F-NMR measurements for the cellular detection of the titanium(IV) complexes. Fluorinated compounds are rarely found in biological systems; thus, tracking fluorinated derivatives of the relevant complexes by ¹⁹F-NMR provides a distinctive and effective way for cellular detection. Moreover, addition of appropriate internal standard, such as triflurotoluene, in a known concentration affords both accurate calibration and quantification of the detected compound in the cell.

Herein we present the ¹⁹F-NMR measurements of cells that were exposed to a fluorinated derivative of the bis(phenolato)bis(alkoxo) Ti(IV) complex. The preliminary results displayed one major species, which is identical to the administered complex. Furthermore, nuclei and mitochondria extracts of the treated cells showed evidence of a fluorinated compound, suggesting that these organelles may present at least one of the cellular targets. Aspects of quantification will be discussed.