Terephthalamide-containing ligands: fast removal of iron from transferrin.
The mechanism and effectiveness of iron removal from transferrin by three series of new potential therapeutic iron sequestering agents have been analyzed with regard to the structures of the chelators. All compounds are hexadentate ligands composed of a systematically varied combination of methyl-3,2-hydroxypyridinone (Me-3,2-HOPO) and 2,3-dihydroxyterephthalamide (TAM) binding units linked to a polyamine scaffold through amide linkers; each series is based on a specific backbone: tris(2-aminoethyl)amine, spermidine, or 5-LIO(TAM), where 5-LIO is 2-(2-aminoethoxy)ethylamine. Rates of iron removal from transferrin were determined spectrophotometrically for the ten ligands, which all efficiently acquire ferric ion from diferric transferrin with a hyperbolic dependence on ligand concentration (saturation kinetics). The effect of the two iron-binding subunits Me-3,2-HOPO and TAM and of the scaffold structures on iron removal ability is discussed. At the low concentrations corresponding to therapeutic dose, TAM-containing ligands exhibit the fastest rates of iron removal, which correlates with their high affinity for ferric ion and suggests the insertion of such binding units into future therapeutic chelating agents. In addition, urea polyacrylamide gel electrophoresis was used to measure the individual microscopic rates of iron removal from the three iron-bound transferrin species (diferric transferrin, N-terminal monoferric transferrin, C-terminal monoferric transferrin) by the representative chelators 5-LIO(Me-3,2-HOPO)(2)(TAM) and 5-LIO(TAMmeg)(2)(TAM), where TAMmeg is 2,3-dihydroxy-1-(methoxyethylcarbamoyl)terephthalamide. Both ligands show preferential removal from the C-terminal site of the iron-binding protein. However, cooperative effects between the two binding sites differ with the chelator. Replacement of hydroxypyridinone moieties by terephthalamide groups renders the N-terminal site more accessible to the ligand and may represent an advantage for iron chelation therapy.
Abergel
Rebecca J
RJ
Department of Chemistry, University of California, Berkeley, CA, 94720-1460, USA.
Raymond
Kenneth N
KN
D000577:Amides / Q000494:pharmacology; D001667:Binding, Competitive; D002396:Catechols / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007501:Iron / Q000302:isolation & purification* / Q000378:metabolism*; D007502:Iron Chelating Agents; D007700:Kinetics; D008024:Ligands; D010795:Phthalic Acids / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013379:Substrate Specificity; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*
C435763:2,3-dihydroxyterephthalamide; D000577:Amides; D002396:Catechols; D007502:Iron Chelating Agents; D008024:Ligands; D010795:Phthalic Acids; D011728:Pyridones; D014168:Transferrin; C032279:phthalic acid; D007501:Iron; C034221:catechol