Intramolecular Weak Interactions in the Thermodynamic Stereoselectivity of Copper(II) Complexes with Carnosine–Trehalose Conjugates

Abstract

The interactions of metal ions with chiral molecules are of particular interest for relevant biochemical processes, as many of them are made possible only with a selected chirality of the stereocenters. In this work we report a study of the stereoselectivity of copper(II) complexes with D-trehalose-L-carnosine and D-trehalose-D-carnosine as a prototypical case of natural chirality selection. The interest in L-carnosine dipeptide is compounded by its antioxidant and antitumor properties, which are further enhanced when combined with D-trehalose. Potentiometric, calorimetric, and UV/circular dichroism (CD) spectroscopic measurements show that the copper(II) dimer of D-trehalose-L-carnosine is more stable than the D-trehalose-D-carnosine diastereoisomeric copper(II) dimer (log β(L)(22-2) - log β(D)(22-2) = 3.6). Free-energy calculations highlight that the cause of this different behavior lies with different intramolecular weak interactions between the diastereoisomers. The different pattern of hydrogen bonds and the different CH-π interactions between the π-electron-rich imidazole and the α-glucose rings are more favorable by 5 kcal mol(-1) in the L dimer.

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“…An analogous protection from carnosinase-induced hydrolysis has also been reported for the Car derivative linked to Tr via the amino group (TrCar1). [25,31] Altogether, these results demonstrate that both the carboxyl and primary amino groups of carnosine are crucial to carnosinase recognition and, hence, for the peptide hydrolysis.…”

“…Determining the binding affinity of Car derivatives [25,26,34] for Cu 2+ is crucial to understand the involvement of such systems in pathologies whose neurotoxicity depends on endogenous metal ions. Thus, the binding affinity of TrCar2 for Cu 2+ was evaluated (Table 2) and compared to that of the analogous derivative TrCar1 [25] and to the parent ligand Car.…”

“…This choice was driven by the need to redress the reactivity limitations resulting from the presence of secondary amines that characterized the carnosine derivatives previously studied. [25,34,35] TrCar2 and its copper(II) complexes were characterized by means of potentiometric as well as spectroscopic (UV-visible (UV-vis), circular dichroism (CD), and EPR) techniques. The antioxidant activity of TrCar2 copper(II) complexes was tested via a superoxide dismutase indirect assay and was compared to that of the analogous complexes with TrCar1 ( Figure 1) and its parent ligand.…”

“…The antioxidant activity of TrCar2 copper(II) complexes was tested via a superoxide dismutase indirect assay and was compared to that of the analogous complexes with TrCar1 ( Figure 1) and its parent ligand. [25] The resistance of the new derivative to the CN1 activity was also assayed.…”

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“…5, 21) (Grasso et al 2011a) and trehalose (22) (Grasso et al 2011b) have also been reported. In these cases, the dimeric species showed a significantly lower stability constant than those reported for the analogs of derivatives with L-Car (Table 1).…”