Redox potentials of Ti(IV) and Fe(III) complexes provide insights into titanium biodistribution mechanisms

Siburt, Claire J. Parker; Lin, Emily M.; Brandt, Sara J.; Tinoco, Arthur D.; Valentine, Ann M.; Crumbliss, Alvin L.

doi:10.1016/j.jinorgbio.2010.04.004

Cited by 19 publications

(16 citation statements)

References 37 publications

(45 reference statements)

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“…4a). This finding complements a positron emission tomography study performed on EMT-6 tumor-bearing BALB/c mice that showed 45 Ti(IV)-sTf uptake into the tumor cells following Ti-citrate administration. 42 These results demonstrate that TfR is able to recognize an open-conformation of metal-bound sTf…”

Section: Resultssupporting

confidence: 83%

“…36,44 The reduction of Ti(IV) as a release mechanism from sTf within the endosome is not feasible. 45 The higher affinity to sTf that Ti(IV) possesses versus Fe(III) at pH 5.5 suggests that a powerful chelator will have to remove Ti(IV). Sadler et al proposed that such a ligand could be ATP 34 although no in vivo studies have been performed to confirm a chelation release mechanism.…”

Section: Resultsmentioning

confidence: 99%

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Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity

Tinoco¹,

Saxena²,

Sharma³

et al. 2016

J. Am. Chem. Soc.

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119

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Human serum transferrin (sTf) is a protein that mediates the transport of iron from blood to cells. Assisted by the synergistic anion carbonate sTf transports Fe(III) by binding the metal ion in a closed conformation. Previous studies suggest sTf’s role as a potential transporter of other metals like titanium. Ti is a widely used metal in colorants, foods, and implants. A substantial amount of Ti is leached into blood from these implants. However, the fate of the leached Ti and its transport into the cells is not known. Understanding Ti interaction with sTf assumes a greater significance with our ever increasing exposure to Ti in the form of implants. Based on in vitro studies it was speculated that transferrin can bind Ti(IV) assisted by a synergistic anion. However, the role and identity of the synergistic anion(s) and the conformational state in which sTf binds Ti(IV) are not known. Here we have solved the first X-ray crystal structure of a Ti(IV)-bound sTf. We find that sTf binds Ti(IV) in an open conformation with both carbonate and citrate as synergistic anions at the metal binding sites, an unprecedented role for citrate. Studies with cell lines suggest that Ti(IV)-sTf is transported into cells and that sTf and citrate regulate the metal’s blood speciation and attenuate its cytotoxic property. Our results provide the first glimpse into the citrate-transferrin synergism in the regulation of Ti(IV) bioactivity and offers insight into the future design of Ti(IV)-based anticancer drugs.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity

Tinoco¹,

Saxena²,

Sharma³

et al. 2016

J. Am. Chem. Soc.

Self Cite

119

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“…These data, in total, reveal that deferasirox and BHPT coordinative saturation highly stabilizes Ti(IV) against dissociation, precipitation, and changes in oxidation much like the case for STf. 29,48,49 This stabilization effect is even superior to another cTfm ligand, N , N ′-bis( o -hydroxybenzyl)ethylenediamine- N , N ′-diacetic acid (HBED), used in previous studies by Tinoco et al, 49,50 which at concentrations between low micromolar to low millimolar serves as a tetraanionic hexadentate ligand at very acidic pH values but undergoes partial intramolecular dissociation due to metal hydrolysis in the pH 5.0–7.4 range. The Ti(IV) deferasirox and BHPT complexes are also more stable than Tshuva et al’s recently produced Ti(IV) complexes of N , N ′-phenolate-substituted HBED derivative ligands, which after a few days in solution begin to exhibit hydrolytic behavior.…”

Section: Resultsmentioning

confidence: 99%

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

et al. 2017

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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.

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“…43 Thus, the heterometallic compounds previously described 39−41 could potentially break into monometallic species in physiological media or in vivo before reaching the tumors. We hypothesized that incorporating the second metal to a ligand strongly bound to the titanium(IV) center would ensure that heterometallic Ti–M species remain after the Ti–Cp hydrolysis takes place under physiological pH conditions.…”

Section: Introductionmentioning

confidence: 99%

Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

et al. 2014

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Early–late transition metal TiAu2 compounds [(η-C5H5)2Ti{OC(O)CH2PPh2AuCl}2] (3) and new [(η-C5H5)2Ti{OC(O)-4-C6H4PPh2AuCl}2] (5) were evaluated as potential anticancer agents in vitro against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold(I) [{HOC(O)RPPh2}AuCl] (R = −CH2– 6, −4-C6H4– 7) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for 5 in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells in vitro coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC503 = 91 nM, IC505 = 117 nM). The selectivity of the compounds in vitro against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially 5) are excellent candidates for further development as potential renal cancer chemotherapeutics.

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Redox potentials of Ti(IV) and Fe(III) complexes provide insights into titanium biodistribution mechanisms

Cited by 19 publications

References 37 publications

Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity

Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

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