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.
The structure of the title compound, [Fe(C5H5)(C15H13O2)], consists of a ferrocenyl moiety and a 2-methoxyphenyl group linked through a prop-2-en-1-one spacer in anEconformation. In the ferrocene unit, the substituted cyclopentadienyl (Cps) ring and the unsubstituted cyclopentadienyl ring (Cp) are almost parallel to one another [dihedral angle = 1.78 (14)°], and the Cp and Cps rings are in agaucheconformation. The benzene ring is twisted by 10.02 (14) and 11.38 (11)° with respect to the Cp and Cps rings, respectively. In the crystal, molecules are linked by weak C—H...O hydrogen bonds into supramolecular chains running along theb-axis direction.
A recently resolved structure of Ti(IV) bound human serum transferrin (sTf) and cell viability studies reveal that the small molecule citrate and the iron(III) transport protein sTf work together to maintain Ti(IV) in a nontoxic speciation in the body. Identification of this biomolecular interaction elucidates important factors that must be considered when developing Ti(IV)-based anticancer agents. Chemical transferrin mimetic (cTfm) ligands are being employed in a Ti(IV) anticancer drug design strategy to take advantage of the structural features of the sTf metal binding site favorable for Ti(IV) coordination to facilitate Ti(IV) cytotoxicity. The very strong Fe(III) binding property of these ligands are exploited to create stable Ti(IV) complexes that are able to deliver Ti(IV) into cells but exhibit lability in the presence of Fe(III). These complexes are intended to operate by the dual function of iron depletion and Ti(IV) attack at intracellular sites. Work with the cTfm ligands N,N’-di(o-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid (HBED) and deferasirox reveal the structural features of the cTfm ligands that maximize the stability of the Ti(IV) complex outside the cell but enable sufficient lability to trigger cytotoxicity within the cell. The features are those that minimize induced dissociation due to the presence of citrate and sTf. Preliminary results suggest that while Fe(III) depletion may play an important role in the activity of the Ti(IV) cTfm complexes, the two lead complexes may operate via different mechanisms of action. Citation Format: Arthur D. Tinoco, Sergio A. Loza-Rosas, Alexandra Vazquez, Kennett I. Rivero, Lenny M. Negron, Manoj Saxena, Shweta Sharma, Yamixa Delgado, Annelis Sanchez, Nicole Zambrana, Timothy B. Parks. Titanium(IV) regulation by serum transferrin and citrate sheds new insight into the use of chemical transferrin mimetics for Ti(IV) anticancer drug development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3105A.
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