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 -type cyclodextrin (CD) derivatives, , and , 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 ( 2 to 3, mainly 3 and 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 > > . (1)H NMR molecular relaxivity measurements for the Gd(iii) complexes of , or 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 and 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.

Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

“…It has been suggested that Gd@C 82 (OH) 22 has potential both as diagnostic and as therapeutic agent [455]. The number of hydroxylic groups should be kept below 36; higher hydroxylated compounds easily form unstable opencaged structures, leading to release Gd 3+ ions in vivo [456].…”

Anionic cyclodextrins as versatile hosts for pharmaceutical nanotechnology: Synthesis, drug delivery, enantioselectivity, contrast agents for MRI

“…of calcium, iron and copper) (Chatain et al, 2004;Trotta et al, 2001) and for the preparation of Ag nanoclusters, which exhibit strong antimicrobial ability in vitro (Wang et al, 2013). Their most remarkable property is the binding of lanthanide cations that makes them potential contrast agents for Magnetic Resonance Imaging (MRI) (Kotková et al, 2012;Maffeo et al, 2010) one of the most powerful diagnostic methods. The above examples suggest that future nano-bioapplications of anionic CD derivatives hold great promises, thus current research explores both synthesis of smart derivatives and diverse areas of possible applications.…”

“…Thus, per(2,3-di-Omethyl-6-amino-6-deoxy)-α-, β-and γ-CDs reacted with t-butyl bromoacetate to a afford, after subsequent deprotection in trifluoroacetic acid, compounds 13a-c (Maffeo et al, 2010) that have the ability to coordinate strongly with lanthanide ions (vide infra 5.2.1).…”

“…Specifically, the derivatives form multimetal complexes, as 13c binds exactly four metal ions (Figure 6), 13b binds mainly three and 13a two to three metal ions (Maffeo et al, 2010 The β-CD derivative with DTPA binds seven Gd(III) (14.Gd(III)) or Eu(III) cations (Scheme 14), each cation associating with an average of 1.8 exchangeable water molecules (Bryson et al, 2008). This metal cluster yielded high relaxivity properties [43.4 mM -1 s -1 per molecule corresponding to 6.2 mM -1 s -1 per Gd(III) cation at 9.4…”

“…The anionic CDs 13a-c (Maffeo et al, 2010) (Scheme 6) that carry iminodiacetic acid groups, feature the ethylenediaminetetraacetic acid (EDTA) chelation ability to form strong complexes with Eu(III), Tb(III), and Gd(III) ions.…”