Abstract
Titanium(IV) anticancer complexes are promising candidates for treatment of various cancers, and previous studies have pointed to possible interactions between Ti(IV) anticancer complexes and the serum proteins albumin and transferrin. Herein, we explored the binding of phenolaTi, a leading diaminobis(phenolato)bis(alkoxo) Ti(IV) anticancer complex, to serum proteins, and derived the binding constants and thermodynamic parameters. The results were compared with those obtained for a salan Ti(IV) bis(isopropoxo) complex and titanocene dichloride, studied under similar conditions. Human serum albumin (HSA) binds phenolaTi in a spontaneous, exothermic process, with a dissociation constant (Kd) of 47 ± 7 μM at room temperature. In the presence of transferrin, the Kd of phenolaTi increases by 2-fold, reflecting the competition between the two proteins over the complex, which was more dominant for the other, less hydrolytically stable complexes tested. Examining the kinetics of the binding, it reaches a maximum after ca. 6 h, and the bond partially dissociates after 24–36 h, presumably due to partial ligand hydrolysis in the absence of cells; nevertheless, the proteins HSA and transferrin have a negligible effect on cytotoxicity after 72 h of incubation, with a possible negative impact on cell entry at short incubation periods. Overall, HSA serves as a carrier for phenolaTi through both its known drug binding sites, presumably in its intact form, which is the species that actively penetrates the cells and inflects cytotoxicity.
Original language | American English |
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Article number | 111817 |
Journal | Journal of Inorganic Biochemistry |
Volume | 232 |
DOIs | |
State | Published - Jul 2022 |
Bibliographical note
Funding Information:Funding was received from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 681243 ). Zohar Shpilt is supported by the Dalia and Dan Maydan Fellowship.
Publisher Copyright:
© 2022 The Authors
Keywords
- Cisplatin
- Cytotoxicity
- Metallodrugs
- Serum proteins
- Titanium(IV)
- Titanocene dichloride