Applying the Fe(III) Binding Property of a Chemical Transferrin Mimetic to Ti(IV) Anticancer Drug Design

Abstract

As an endogenous serum protein binder of Ti­(IV), transferrin (Tf) serves as an excellent vehicle to stabilize the hydrolysis prone metal ion and successfully transport it into cells. This transporting role is thought to be central to Ti­(IV)’s anticancer function, but efforts to synthesize Ti­(IV) compounds targeting transferrin have not produced a drug. Nonetheless, the Ti­(IV) transferrin complex (Ti₂Tf) greatly informs on a new Ti­(IV)-based anticancer drug design strategy. Ti₂Tf interferes with cellular uptake of Fe­(III), which is particularly detrimental to cancer cells because of their higher requirement for iron. Ti­(IV) compounds of chemical transferrin mimetic (cTfm) ligands were designed to facilitate Ti­(IV) activity by attenuating Fe­(III) intracellular levels. In having a higher affinity for Fe­(III) than Ti­(IV), these ligands feature the appropriate balance between stability and lability to effectively transport Ti­(IV) into cancer cells, release Ti­(IV) via displacement by Fe­(III), and deplete the intracellular Fe­(III) levels. The cTfm ligand <i>N,N</i>′-di­(<i>o</i>-hydroxybenzyl)­ethylenediamine-<i>N,N</i>′-diacetic acid (HBED) was selected to explore the feasibility of the design strategy. Kinetic studies on the Fe­(III) displacement process revealed that Ti­(IV) can be transported and released into cells by HBED on a physiologically relevant time scale. Cell viability studies using A549 cancerous and MRC5 normal human lung cells and testing the cytotoxicity of HBED and its Ti­(IV), Fe­(III), and Ga­(III) compounds demonstrate the importance of Fe­(III) depletion in the proposed drug design strategy and the specificity of the strategy for Ti­(IV) activity. The readily derivatized cTfm ligands demonstrate great promise for improved Ti­(IV) anticancer drugs