Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes
| Autor: | Yamixa Delgado, Timothy B. Parks, Angel L. Vazquez-Maldonado, Lenny J. Negrón, Arthur D. Tinoco, Josué A. Benjamín-Rivera, Sergio A. Loza-Rosas, Charlene Munet-Colón, Alexandra M. Vázquez-Salgado, Kennett I. Rivero |
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| Rok vydání: | 2017 |
| Předmět: |
Iron
Potentiometric titration Inorganic chemistry Antineoplastic Agents Apoptosis Iron Chelating Agents Ligands 010402 general chemistry Benzoates 01 natural sciences Article Inorganic Chemistry Metal Drug Stability Coordination Complexes Cell Line Tumor medicine Humans Physical and Theoretical Chemistry Serum Albumin Titanium chemistry.chemical_classification Aqueous solution Molecular Structure 010405 organic chemistry Ligand Deferasirox Transferrin Triazoles 0104 chemical sciences Bioavailability Models Chemical chemistry Drug Design visual_art visual_art.visual_art_medium Nuclear chemistry medicine.drug |
| Zdroj: | Inorganic Chemistry. 56:7788-7802 |
| ISSN: | 1520-510X 0020-1669 |
| DOI: | 10.1021/acs.inorgchem.7b00542 |
| Popis: | The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion reveals a difference in Ti(IV) coordination versus iron(III), the metal endogenously delivered by the protein to cells. This finding enriches our bioinspired drug design strategy for Ti(IV)-based anticancer therapeutics, which applies a family of Fe(III) chelators termed chemical transferrin mimetic (cTfm) ligands to inhibit Fe bioavailability in cancer cells. Deferasirox, a drug used for iron overload disease, is a cTfm ligand that models STf coordination to Fe(III), favoring Fe(III) binding versus Ti(IV). This metal affinity preference drives deferasirox to facilitate the release of cytotoxic Ti(IV) intracellularly in exchange for Fe(III). An aqueous speciation study performed by potentiometric titration from pH 4 to 8 with micromolar levels of Ti(IV) deferasirox at a 1:2 ratio reveals exclusively Ti(deferasirox)2 in solution. The predominant complex at pH 7.4, [Ti(deferasirox)2]2−, exhibits the one of the highest aqueous stabilities observed for a potent cytotoxic Ti(IV) species, demonstrating little dissociation even after 1 month in cell culture media. UV–vis and 1H NMR studies show that the stability is unaffected by the presence of biomolecular Ti(IV) binders such as citrate, STf, and albumin, which have been shown to induce dissociation or regulate cellular uptake and can alter the activity of other antiproliferative Ti(IV) complexes. Kinetic studies on [Ti(deferasirox)2]2− transmetalation with Fe(III) show that a labile Fe(III) source is required to induce this process. The initial step of this process occurs on the time scale of minutes, and equilibrium for the complete transmetalation is reached on a time scale of hours to a day. This work reveals a mechanism to deliver Ti(IV) compounds into cells and trigger Ti(IV) release by a labile Fe(III) species. Cellular studies including other cTfm ligands confirm the Fe(III) depletion mechanism of these compounds and show their ability to induce early and late apoptosis. |
| Databáze: | OpenAIRE |
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