Synthesis, conformational analysis and biological activity of xylopyranosyl sulfur-containing glycosides: dependence of sulfur atom configuration†

Proteoglycans (PGs) consist of a core protein with covalently bound glycosaminoglycan (GAG) chains that are linked via a tetrasaccharide. PGs are important macromolecules that are involved in biological processes such as cell growth and differentiation. A key enzyme in the biosynthesis of PG GAG chains is β-1,4-galactosyltransferase 7 (β4GalT7) that catalyzes the transfer of galactose to a xylose residue in the formation of the linker tetrasaccharide. It is well known that the addition of xylosides containing naphthyl aglycones can initiate the biosynthesis of GAG chains by acting as substrates for β4GalT7. Previous studies have shown that its galactosylation ability is increased by using bioisosters, in which the anomeric oxygen is replaced with sulfur or sulfur-containing functional groups. Thus, 2-naphthyl xylosyl sulfoxides were synthesized and characterized by ¹H and ¹³C NMR spectroscopy relying on both one- and two-dimensional experiments to differentiate the stereochemistry at the sulfur atom. Notably, the conformationally dependent ³J_CH coupling constants between the anomeric proton and the C2′ atom of the naphthyl group were large and significant, ≥3.3 Hz, for the (S)_S-configured compound as well as for the O-glycoside and the thio-derivative whereas the corresponding coupling for the (R)_S-configured compound and the sulfone derivative had ³J_C2′,H1 < 0.6 Hz and ³J_C2′,H1 < 0.5 Hz, respectively. Quantum mechanical calculations of the ³J_C2′,H1 coupling constant corroborated the experimentally observed trends at the ϕ torsion angle. The galactosylation by β4GalT7 of the different acceptor substrates showed the highest affinity for the (R)_S-configured compound and the sulfone derivative whereas an intermediate affinity was present for the (S)_S-configured compound and the thio-derivative. The enzyme efficiency exhibited with the latter substrate was more than three times higher than with any other of the thio-derivatives. From molecular docking of the acceptor substrates to the UDP-galactose:β4GalT7 complex specific intermolecular interactions were identified. The binding affinity correlates with stacking to a tyrosine residue and a weak C–H⋯O hydrogen bond between the indole group of tryptophan in the enzyme and a proximate oxygen atom of sulfone and sulfinyl derivatives of 2-naphthyl xylosides.