Remarkable differences and similarities between the isomeric Mn(II)- cis - and trans- 1,2-diaminocyclohexane- N , N , N ′, N ′-tetraacetate complexes

Abstract : Equilibrium, kinetic (solvent exchange and dissociation of the complex) and relaxometric studies (1H and 17O NMR) have been performed with the [M(II)(c-cdta)]2− complexes (c-cdta = cis-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid, M(II) = Mn(II), Zn(II), Cu(II),Ca(II), Mg(II)) and the physico-chemical data are compared to the isomeric complexes with trans-1,2-cdta (t-cdta) with the aim of searching appropriate ligands for Mn(II) complexation for safe MRI contrast agents. The total basicity (Σ log KiH) of the c-cdta ligand appears to be very similar to that of the trans-derivative under the conditions applied (I = 0.15 M NaCl and 25 °C), but the first two protonation constants notably differ. log K1H is 1.5 log units higher, while the log K2H is 0.8 log units lower than those determined for the trans-derivative. Similar basicity of the ligands results in similar complex stability (log K[Mn(L)] values are 14.19(2) and 14.32), whereas the conditional stabilities near to physiological pH are different (pMn values are 7.82 and 8.68) for the [Mn(c-cdta)]2− and the [Mn(t-cdta)]2− derivatives, respectively. Dissociation kinetic studies revealed that the [Mn(c-cdta)]2− dissociates 250 times faster than the [Mn(t-cdta)]2− complex. The water exchange rate (kex298) of [Mn(c-cdta)]2− is ca. 60% higher than that of [Mn(t-cdta)]2−. The differences can likely be attributed to the different distances between the individual donor atoms, and the arrangement of the donor atoms around the metal ions in the cis- and trans- isomers. Interestingly, the relaxivity values of the Mn(II) complexes are very close (r1p = 3.79 mM−1 s−1 and 3.62 mM−1 s−1; 20 MHz, 25 °C for the cis- and trans-isomers, respectively). DFT calculations were used to gain insight into the different properties of the [Mn(c-cdta)]2− and the [Mn(t-cdta)]2− complexes. The results gained in our studies confirm that the trans-1,2-cyclohexanediamine “building block” displays better features for further ligand development. Graphical abstract M(II) complexes formed with c-cdta (cis-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid) chelator have been investigated by pH-potentiometry, UV–vis spectrophotometry, DFT calculations,1H- and 17O-NMR relaxometry. pMn as well as the inertness of the Mn(II) complex formed with c-cdta ligand were found to differ substantially form those found for the trans-derivative while the water exchange rate and the relaxivity do not differ remarkably. Our results confirm, that the t-cdta platform has better potential for further ligand development owing to better dissociation kinetic parameters of its Mn(II) complex.
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Enikő Molnár, Balázs Váradi, Zoltán Garda, Richárd Botár, Ferenc Kálmán, et al.. Remarkable differences and similarities between the isomeric Mn(II)- cis - and trans- 1,2-diaminocyclohexane- N , N , N ′, N ′-tetraacetate complexes. Inorganica Chimica Acta Reviews, Elsevier, 2018, 472, pp.254-263. ⟨hal-01966166⟩



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