Coordination modes between copper(II) and N-acetylneuraminic (Sialic) acid from a 2D-simulation analysis of EPR spectra. Implications for copper mediation of sialoglycoconjugate chemistry relevant to human biology

The equilibrium distribution of species formed between Cu(II) and N-acetylneuraminic (sialic) acid (I, LH) at 298 K has been determined using a two-dimensional (2D) simulation analysis of electron paramagnetic resonance (EPR) spectra. In acidic solutions (pH values 11. It is proposed that [CuL] + most likely features I coordinated via the deprotonated carboxylic acid group (O 1 ) and the endocyclic oxygen atom (OR) forming a five-membered chelate ring. Select Cu(II)-I species of the form [CuLH - 1 ] may feature I acting as a dianionic tridentate chelate, via oxygen atoms derived from O 1 , OR, and one deprotonated hydroxy group (O 7 or O 8 ) from the glycerol tail. Alternatively, I may coordinate Cu(II) in a bidentate fashion as the tert-2-hydroxycarboxylato (O 1 ,O 2 ) dianion. Spectra predicted for Cu(II)-I complexes in which I is coordinated in either a O 1 ,O R {I(1-)} or O 1 ,O 2 {I(2-)} bidentate fashion {e.g., [CuL] + (O 1 ,O R ), [CuL 2 ] (bis-O 1 ,O R ), [CuLH - 1 ] (isomer: O 1 ,O 2 ), [CuL 2 H - 1 ] - (O 1 ,O R ; O 1 ,O 2 ), and [CuL 2 H - 2 ] 2 - (isomer: bis-O 1 ,O 2 )} have "irregular" EPR spectra that are ascribed to the existence of Cu(II)-I(monomer) ⇄ Cu(II)-I(polymer) equilibria. The formation of polymeric Cu(II)-I species will be favored in these complexes because the glycerol-derived hydroxyl groups at the complex periphery (O, 7 O, 8 O 9 ) are available for further Cu(II) binding. The presence of polymeric Cu(II)-I species is supported by EPR spectral data from solutions of Cu(II) and the homopolymer of I, colominic acid (I p o l y ). Conversely, spectra predicted for Cu(II)-I complexes where I is coordinated in a {I(2-)} tridentate {e.g., [CuLH - 1 ] (isomer: O 1 ,O R ,O 7 , or O 8 ) and [CuL 2 H - 2 ] 2 - (isomer: bis-O 1 ,O R ,O 7 , or O 8 )} or tetradentate fashion {I(3-)} {e.g., [CuLH - 3 ] 2 - (O 1 ,O R ,O, 8 C 9 )} are typical for mononuclear tetragonally elongated Cu(II) octahedra. In this latter series of complexes, the tendency toward the formation of polymeric Cu(II)-I analogues is small because the polydentate I effectively wraps up the mononuclear Cu(II) center. This work shows that Cu(II) could potentially mediate the chemistry of sialoglycoconjugate-containing proteins in human biology, such as the sialylated amyloid precursor protein of relevance to Alzheimer's disease.