Publicação

Complexes of bifunctional DO3A-N-(α-amino)propinate ligands with Mg(II), Ca(II), Cu(II), Zn(II), and lanthanide(III) ions: thermodynamic stability, formation and dissociation kinetics, and solution dynamic NMR studies

Detalhes bibliográficos
Resumo:	The thermodynamic, kinetic, and structural properties of Ln<sup>3+</sup> complexes with the bifunctional DO3A-ACE<sup>4−</sup> ligand and its amide derivative DO3A-BACE<sup>4−</sup> (modelling the case where DO3A-ACE<sup>4−</sup> ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd<sup>3+</sup> complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg<sup>2+</sup> and Ca<sup>2+</sup> complexes of DO3A-ACE<sup>4−</sup> and DO3A-BACE<sup>4−</sup> complexes are lower than for DOTA<sup>4−</sup> and DO3A<sup>3−</sup>, while the Zn<sup>2+</sup> and Cu<sup>2+</sup> complexes have similar and higher stability than for DOTA<sup>4−</sup> and DO3A<sup>3−</sup> complexes. The stability constants of the Ln(DO3A-BACE)<sup>−</sup> complexes increase from Ce<sup>3+</sup> to Gd<sup>3+</sup> but remain practically constant for the late Ln<sup>3+</sup> ions (represented by Yb<sup>3+</sup>). The stability constants of the Ln(DO3A-ACE)<sup>4−</sup> and Ln(DO3A-BACE)<sup>4−</sup> complexes are several orders of magnitude lower than those of the corresponding DOTA<sup>4−</sup> and DO3A<sup>3−</sup> complexes. The formation rate of Eu(DO3A-ACE)<sup>−</sup> is one order of magnitude slower than for Eu(DOTA)<sup>−</sup>, due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE)<sup>−</sup> complexes to dissociate several orders of magnitude faster than Ln(DOTA)<sup>−</sup> and its absence in the Ln(DO3A-BACE)<sup>−</sup> complexes results in inertness similar to Ln(DOTA)<sup>−</sup> (as judged by the rate constants of acid assisted dissociation). The <sup>1</sup>H NMR spectra of the diamagnetic Y(DO3A-ACE)<sup>−</sup> and Y(DO3A-BACE)<sup>−</sup> reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-<i>Λ</i>(<i>λλλλ</i>) and S-<i>Δ</i>(<i>δδδδ</i>). The conformation of the C<sub>α</sub>-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE)<sup>−</sup> than the amino group in Y(DO3A-ACE)<sup>−</sup> to minimize steric hindrance. The temperature dependence of the spectra reflects slower ring motions than pendant arms rearrangements in both complexes. Although losing some thermodynamic stability relative to Gd(DOTA)<sup>−</sup>, Gd(DO3A-BACE)<sup>−</sup> is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE<sup>4−</sup> in the design of GBCAs and Ln<sup>3+</sup>-based tags for protein structural NMR analysis.
Autores principais:	Garda, Zoltán
Outros Autores:	Kócs, Tamara; Bányai, István; Martins, J. A. R.; Kálmán, Ferenc Krisztián; Tóth, Imre; Geraldes, Carlos F. G. C.; Tircsó, Gyula
Assunto:	Bifunctional ligands (BFCs) Complexes Equilibrium Formation and dissociation kinetics Dynamic NMR
Ano:	2021
País:	Portugal
Tipo de documento:	artigo
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade do Minho
Idioma:	inglês
Origem:	RepositóriUM - Universidade do Minho

Descrição
Resumo:	The thermodynamic, kinetic, and structural properties of Ln<sup>3+</sup> complexes with the bifunctional DO3A-ACE<sup>4−</sup> ligand and its amide derivative DO3A-BACE<sup>4−</sup> (modelling the case where DO3A-ACE<sup>4−</sup> ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd<sup>3+</sup> complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg<sup>2+</sup> and Ca<sup>2+</sup> complexes of DO3A-ACE<sup>4−</sup> and DO3A-BACE<sup>4−</sup> complexes are lower than for DOTA<sup>4−</sup> and DO3A<sup>3−</sup>, while the Zn<sup>2+</sup> and Cu<sup>2+</sup> complexes have similar and higher stability than for DOTA<sup>4−</sup> and DO3A<sup>3−</sup> complexes. The stability constants of the Ln(DO3A-BACE)<sup>−</sup> complexes increase from Ce<sup>3+</sup> to Gd<sup>3+</sup> but remain practically constant for the late Ln<sup>3+</sup> ions (represented by Yb<sup>3+</sup>). The stability constants of the Ln(DO3A-ACE)<sup>4−</sup> and Ln(DO3A-BACE)<sup>4−</sup> complexes are several orders of magnitude lower than those of the corresponding DOTA<sup>4−</sup> and DO3A<sup>3−</sup> complexes. The formation rate of Eu(DO3A-ACE)<sup>−</sup> is one order of magnitude slower than for Eu(DOTA)<sup>−</sup>, due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE)<sup>−</sup> complexes to dissociate several orders of magnitude faster than Ln(DOTA)<sup>−</sup> and its absence in the Ln(DO3A-BACE)<sup>−</sup> complexes results in inertness similar to Ln(DOTA)<sup>−</sup> (as judged by the rate constants of acid assisted dissociation). The <sup>1</sup>H NMR spectra of the diamagnetic Y(DO3A-ACE)<sup>−</sup> and Y(DO3A-BACE)<sup>−</sup> reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-<i>Λ</i>(<i>λλλλ</i>) and S-<i>Δ</i>(<i>δδδδ</i>). The conformation of the C<sub>α</sub>-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE)<sup>−</sup> than the amino group in Y(DO3A-ACE)<sup>−</sup> to minimize steric hindrance. The temperature dependence of the spectra reflects slower ring motions than pendant arms rearrangements in both complexes. Although losing some thermodynamic stability relative to Gd(DOTA)<sup>−</sup>, Gd(DO3A-BACE)<sup>−</sup> is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE<sup>4−</sup> in the design of GBCAs and Ln<sup>3+</sup>-based tags for protein structural NMR analysis.