From medium to endoplasmic reticulum: Tracing anticancer phenolato titanium(IV) complex by ¹⁹F NMR detection

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Pharmacology

Background:

• Titanium(IV) complexes with diaminobis(phenolato)-bis(alkoxo) ligands exhibit significant in-vivo anticancer efficacy.
• Minimal toxic side-effects observed in preclinical studies necessitate understanding their mechanism of action.

Purpose of the Study:

• To elucidate the mechanism of action of Titanium(IV) complexes as anticancer agents.
• To investigate the biodistribution and cellular targets of a fluoro-substituted derivative, FenolaTi, using quantitative 19F NMR.

Main Methods:

• Utilized quantitative 19F NMR spectroscopy for biodistribution and reactivity analysis.
• Investigated FenolaTi interactions with serum albumin and cellular components.
• Assessed cellular accumulation and localization within extracellular and intracellular compartments.

Main Results:

• FenolaTi interacts with bovine serum albumin in extracellular media.
• Significant cellular accumulation (37%) of FenolaTi derivatives observed, indicating active transport.
• Extracellular FenolaTi originated partly from post-apoptotic cells (19%).
• FenolaTi localized in the nucleus but did not interact with DNA or nuclear proteins.
• High accumulation and protein interaction detected in the endoplasmic reticulum (ER).

Conclusions:

• The endoplasmic reticulum is a potential cellular target for cytotoxic bis(phenolato)-bis(alkoxo) Ti(IV) complexes.
• Active membrane transport facilitates cellular penetration of FenolaTi.
• Quantitative 19F NMR is effective for tracking drug biodistribution and cellular interactions.