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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

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Department of Physical Chemistry, Faculty of Science and Technology, University of Debrecen, H-4010 Debrecen, Hungary
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Centro de Química, Campus de Gualtar, Universidade do Minho, 4710-057 Braga, Portugal
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Department of Life Sciences and Coimbra Chemistry Centre, Faculty of Science and Technology, University of Coimbra, 3000-393 Coimbra, Portugal
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CIBIT/ICNAS-Instituto de Ciências Nucleares Aplicadas à Saúde, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
*
Authors to whom correspondence should be addressed.
Academic Editor: Yongzhong Bian
Molecules 2021, 26(16), 4956; https://doi.org/10.3390/molecules26164956
Received: 9 June 2021 / Revised: 13 July 2021 / Accepted: 15 July 2021 / Published: 16 August 2021
(This article belongs to the Special Issue Recent Advances on MRI Contrast Agents)
The thermodynamic, kinetic, and structural properties of Ln3+ complexes with the bifunctional DO3A-ACE4− ligand and its amide derivative DO3A-BACE4− (modelling the case where DO3A-ACE4− ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd3+ complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg2+ and Ca2+ complexes of DO3A-ACE4− and DO3A-BACE4− complexes are lower than for DOTA4− and DO3A3−, while the Zn2+ and Cu2+ complexes have similar and higher stability than for DOTA4− and DO3A3− complexes. The stability constants of the Ln(DO3A-BACE) complexes increase from Ce3+ to Gd3+ but remain practically constant for the late Ln3+ ions (represented by Yb3+). The stability constants of the Ln(DO3A-ACE)4− and Ln(DO3A-BACE)4− complexes are several orders of magnitude lower than those of the corresponding DOTA4− and DO3A3− complexes. The formation rate of Eu(DO3A-ACE) is one order of magnitude slower than for Eu(DOTA), due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE) complexes to dissociate several orders of magnitude faster than Ln(DOTA) and its absence in the Ln(DO3A-BACE) complexes results in inertness similar to Ln(DOTA) (as judged by the rate constants of acid assisted dissociation). The 1H NMR spectra of the diamagnetic Y(DO3A-ACE) and Y(DO3A-BACE) reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-Λ(λλλλ) and S-Δ(δδδδ). The conformation of the Cα-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE) than the amino group in Y(DO3A-ACE) 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), Gd(DO3A-BACE) is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE4− in the design of GBCAs and Ln3+-based tags for protein structural NMR analysis. View Full-Text
Keywords: bifunctional ligands (BFCs); complexes; equilibrium; formation and dissociation kinetics; dynamic NMR bifunctional ligands (BFCs); complexes; equilibrium; formation and dissociation kinetics; dynamic NMR
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MDPI and ACS Style

Garda, Z.; Kócs, T.; Bányai, I.; Martins, J.A.; Kálmán, F.K.; Tóth, I.; Geraldes, C.F.G.C.; Tircsó, G. 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. Molecules 2021, 26, 4956. https://doi.org/10.3390/molecules26164956

AMA Style

Garda Z, Kócs T, Bányai I, Martins JA, Kálmán FK, Tóth I, Geraldes CFGC, Tircsó G. 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. Molecules. 2021; 26(16):4956. https://doi.org/10.3390/molecules26164956

Chicago/Turabian Style

Garda, Zoltán, Tamara Kócs, István Bányai, José A. Martins, Ferenc K. Kálmán, Imre Tóth, Carlos F.G.C. Geraldes, and Gyula Tircsó. 2021. "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" Molecules 26, no. 16: 4956. https://doi.org/10.3390/molecules26164956

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