Semi-Rigid (Aminomethyl) Piperidine-Based Pentadentate Ligands for Mn(II) Complexation.

Jonathan Martinelli,Lorenzo Tei,Edoardo Callegari,Maurizio Cossi,Alberto Fraccarollo,Zsolt Baranyai

doi:10.3390/molecules26195993

Jonathan Martinelli, Lorenzo Tei + Show 4 more

Open Access

https://doi.org/10.3390/molecules26195993

Copy DOI

Abstract

Two pentadentate ligands built on the 2-aminomethylpiperidine structure and bearing two tertiary amino and three oxygen donors (three carboxylates in the case of AMPTA and two carboxylates and one phenolate for AMPDA-HB) were developed for Mn(II) complexation. Equilibrium studies on the ligands and the Mn(II) complexes were carried out using pH potentiometry, 1H-NMR spectroscopy and UV-vis spectrophotometry. The Mn complexes that were formed by the two ligands were more stable than the Mn complexes of other pentadentate ligands but with a lower pMn than Mn(EDTA) and Mn(CDTA) (pMn for Mn(AMPTA) = 7.89 and for Mn(AMPDA-HB) = 7.07). 1H and 17O-NMR relaxometric studies showed that the two Mn-complexes were q = 1 with a relaxivity value of 3.3 mM−1 s−1 for Mn(AMPTA) and 3.4 mM−1 s−1 for Mn(AMPDA-HB) at 20 MHz and 298 K. Finally, the geometries of the two complexes were optimized at the DFT level, finding an octahedral coordination environment around the Mn2+ ion, and MD simulations were performed to monitor the distance between the Mn2+ ion and the oxygen of the coordinated water molecule to estimate its residence time, which was in good agreement with that determined using the 17O NMR data.

Highlights

Mn2+ is an endogenous metal ion that is involved in several biochemical processes and it is present in serum at concentrations of 0.5–1.2 μg/L [1]
For AMPDA-HB, AMPDA-HB, an an improved improved synthesis synthesis was was developed developed (Scheme (Scheme 1), 1), our where salicylaldehyde was initially protected at its hydroxyl moiety with a methoxymethyl salicylaldehyde was initially protected at its hydroxyl moiety with a methoxyme(MOM)
Mn complex, whereas the ligand with two acetate and one 2-hydroxybenzyl pendants (AMPDA-HB) showed the higher total basicity but lower stability of the metal complex due to the protonation of the phenol group at pH < 6. Both Mn complexes were mono-hydrated with relaxivities in the order of 3.3–3.4 mM−1 s−1

Summary

Introduction

Mn2+ is an endogenous metal ion that is involved in several biochemical processes and it is present in serum at concentrations of 0.5–1.2 μg/L [1]. Require the cation to be “caged” by an organic ligand to prevent undesired side reactions in vivo that would compromise its role and cause toxic effects. Such chelators are normally polyamino-polycarboxylates that are capable of strongly binding the metal ion while leaving at least one free coordination position for an exchangeable water molecule: this is an almost compulsory requirement for having a significant contrast enhancement effect with this type of MRI agent. Since Mn(II) typically forms six- or sevencoordinated complexes, using hexa- or pentadentate chelators (Figure 1) was proposed to Molecules 2021, 26, 5993 changeable water molecule: this is an almost compulsory requirement for having a significant contrast enhancement effect with this type of MRI agent.

Methods

Discussion

Conclusion