title: 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 N,N'-di(o-hydroxybenzyl)ethylenediamine-N,N'-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.
authors.affiliation: Department of Chemistry, University of Puerto Rico, Río Piedras Campus , San Juan, Puerto Rico 00931.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Parks
authors.forename: Yahaira M
authors.initials: YM
authors.lastname: Cruz
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Tinoco
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology; D032701:Biomimetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005290:Ferric Compounds / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D014025:Titanium / Q000737:chemistry* / Q000494:pharmacology; D014168:Transferrin / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005290:Ferric Compounds; D014168:Transferrin; D014025:Titanium