Enantiomeric pairs of copper(ii) complexes with tridentate Schiff bases derived from R- and S-methionine: the role of decorating organic groups of the ligand in crystal packing and biological activity

Abstract

Three enantiomeric pairs consisting of copper(II) complexes with tridentate Schiff bases have been synthesized for employing in biological assessments: ¹_∞[Cu₂(R/S-salmet)₂(H₂O)] (1-R/S·H₂O), ¹_∞[Cu(R/S-3-HOMe-5-Me-salmet)] (2-R/S), and ¹_∞[Cu(R/S-3-MeO-salmet)] (3-R/S) (where R/S-salmetH₂, R/S-3-HOMe-5-Me-salmetH₂, and R/S-3-MeO-salmetH₂ result from the condensation of R/S-methionine with salicylaldehyde, 2-hydroxy-3-(hydroxymethyl)-5-methylbenzaldehyde, and 3-methoxy-salicylaldehyde, respectively, in a 1 : 1 molar ratio). The crystal structures of 1-R·H₂O and 2-R/S are reported. Moreover, the 1-R/S·H₂O enantiomers have been subjected to a single-crystal-to-single-crystal (SC–SC) transformation by heating at 160 °C to afford their dehydrated forms, ¹_∞[Cu₂(R/S-salmet)₂] (1-R/S), whose structures have also been crystallographically determined. The coordination polyhedra of the metal centers, the binding modes of the ligands, and the 1-D double chain assemblies generated by the chiral mononuclear units are comparatively described. The diffuse reflectance UV-Vis and circular dichroism (CD) spectra of compounds 1-R/S·H₂O, 1-R/S, and 2-R/S are analysed with respect to their structural peculiarities and compared to those of 3-R/S. The UV-Vis and CD spectra of solutions of 1-R/S, 2-R/S, and 3-R/S point to the collapse of the double chains via dissolution. Biological tests performed on the model eukaryote Saccharomyces cerevisiae indicated low toxicity for 1-R/S, 2-R/S, and 3-R, and moderate toxicity for 3-S. The S-type complexes were accumulated by cells in higher quantity compared to their R-type counterparts due to selective transport via the high-affinity S-methionine transporter, Mup1. A chemogenomic analysis of 3-S toxicity performed on a collection of yeast knockout mutants revealed that most of the deleted genes identified in the screen were involved in the cell response to oxidative stress, calcium-mediated response, or metal homeostasis. Altogether, it was concluded that 3-S accumulation may perturb the redox state of the cell, also interfering with the calcium-mediated response to oxidative stress or metal-related oxidative stress.