Despite the ubiquitous nature of titanium(IV) and several examples of its beneficial behavior in different organisms, the metal remains under appreciated in biology. The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion, presents a profound difference in Ti(IV) coordination versus iron(III). This enriches the bioinspired drug design strategy for Ti(IV)-based anticancer therapeutics. Deferasirox, a drug designed to treat iron overload disease, serves as a cTfm ligand that models STf coordination to Fe(III) and effectively favors Fe(III) binding versus Ti(IV). The Ti(IV)-deferasirox complex predominant at pH 7.4, [Ti(Deferasirox)2]2-, exhibits the highest aqueous stability observed for a potent cytotoxic Ti(IV) species. This aqueous stability highly depends of the protonation state of the complex. To understand what species will be present at a certain pH value, the dissociation constants for the Ti(IV)-deferasirox complex were determined. Doing an aqueous potentiometric titration and using the chemical equilibrium of the complex, two pKa values were determined. The aqueous solution speciation studies reveal that at concentrations between mid μM to low mM, Ti(Deferasirox)2 remains very stable for a minimum of three days over the broad pH range of 4.3 (the pH if dissolved in water) to 7.4 as indicated by unchanging UV-Vis and 1H NMR spectra of the compound at these pH values. The pH titration curve for Ti(Deferasirox)2 is indicative of a weak diprotic acid with one equivalent of base needed to get each of the inflection points. Due to the symmetrical nature of the compound, the pKa values of the carboxylic acids are very comparable (pKa1= 5.7 ± 0.2 and the pKa2= 5.9 ± 0.3). This alludes the fact that at pH 7.4, the prevalent Ti(IV)-deferasirox complex species is going to be deprotonated species, increasing the complex’s solubility and stability.

Ti(Deferasirox)2, a highly cytotoxic chemical transferrin mimetic Ti(IV)-based compound, displays one of the highest aqueous stabilities in the Ti(IV)-based anticancer field

255th National Meeting (2018)

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