Novel polycarboxylated EDTA-type cyclodextrins as ligands for lanthanide binding: study of their luminescence, relaxivity properties of Gd(iii) complexes, and PM3 theoretical calculations

Abstract

Novel EDTA-type cyclodextrin (CD) derivatives, AEDTA, BEDTA and GEDTA, bearing 6, 7 and 8 bis(carboxymethyl)amino (iminodiacetic acid) groups, respectively, were prepared, and their complexation with Eu(III), Tb(III) and Gd(III) ions was studied. Luminescence titrations and mass spectrometry showed formation of multimetal complexes (AEDTA 2 to 3, BEDTA mainly 3 and GEDTA exactly 4 metal ions), whereas luminescence lifetime measurements revealed the presence of exchangeable water molecules. Semiempirical quantum mechanical calculations, performed by the PM3 method and assessed by DFT calculations on model ligands, indicated efficient multi-metal complexation, in agreement with the experiment. The structures showed coordination of the metal ions in the outer primary side of the CDs via 4 carboxylate O atoms, 2 N atoms and a glucopyranose O atom per metal ion. Coordination of water molecules was also predicted, in accordance with experimental results. Calculated bond lengths and angles were in agreement with literature experimental values of lanthanide complexes. Calculated energies showed that complex stability decreases in the order GEDTA > BEDTA > AEDTA. ¹H NMR molecular relaxivity measurements for the Gd(III) complexes of AEDTA, BEDTA or GEDTA in water afforded values 4 to 10 times higher than the relaxivity of a commercial contrast agent at 12 MHz, and 6 to 20 times higher at 100 MHz. Solutions of BEDTA and GEDTA Gd(III) complexes in human blood plasma displayed relaxivity values at 100 MHz 7 and 12 times, respectively, higher than the commercial agent. MTT tests of the Gd(III) complexes using human skin fibroblasts did not show toxicity. Attempts to supramolecularly sensitize the luminescence of the lanthanide complexes using various aromatic CD guests were ineffective, evidently due to large guest–metal distances and inefficient inclusion. The described lanthanide complexes, could be useful as contrast agents in MRI.