Characterization of copper(II) interactions with sinefungin, a nucleoside antibiotic: combined potentiometric, spectroscopic and DFT studies

Abstract

Interactions between sinefungin and copper(II) ions were investigated. Stoichiometry and stability constants of the metal-free system and two mononuclear complexes present in solution were determined on the basis of potentiometric data analysis. The results were compared to the Cu(II)-ornithine system due to structural similarities between both molecules. Combined spectroscopic and theoretical studies allowed for determination of coordination pattern for the Cu(II)-sinefungin complexes. At acidic pH, copper is bound in "glycine-like" coordination mode, identical with that of ornithine. This involves alpha-amino group and the carboxyl oxygen. At higher pH, a "bis-complex" is formed by two sinefungin molecules. The second ligand binds in equatorial position displacing two water molecules, what results in the stable {2N,2O} coordination. Both axial positions are supposed to be occupied by N1 nitrogen donors of adenine moiety, what is confirmed by DFT calculations. They interact indirectly with copper(II) through water molecules as the result of dominant syn conformation of purine.

Figure 1

The fully protonated molecule of sinefungin in its two conformers, (a) anti and (b) syn.

Figure 2

Conformations of free SFG molecule in various protonation states. The rotation angle of adenine is marked with asterisks.

Figure 3

The differential UV spectrum for the Cu(II)-SFG system obtained by subtraction of the spectrum at pH 3.45 from the spectrum at pH 4.57.

Figure 4

The lowest energy structure of CuH₂L³⁺ complex. The angle O–C–N–C defining the position of adenine group is marked with asterisks.

Figure 5

The pH-dependent courses of complexes concentrations and the (a) CD and (b) UV-Vis spectra parameters overlaid.

Figure 6

The EPR spectra for the Cu(II)-SFG system at pH 5.6. Signals for complex species are indicated by arrows and signals for Cu(II) aqua ion are depicted with asterisks.

Figure 7

The lowest energy structure of CuHL²⁺ complex. The rotation angle of adenine is marked with asterisks.

Figure 8

The lowest energy structures of ${\text{Cu}{\text{H}}_2{\text{L}}_2}^{2+}$ in syn conformation. The angle Cu–N–C–C defining the conformation of SFG at the copper center is marked with asterisks.

Figure 9

Electrostatic potentials of HL and L⁻ in the syn and anti conformations. The potential values are in the range from −0.012 [a.u.] (blue) to 0.05 [a.u.] (red).