Synthesis and biological evaluation of S-simplexides and other analogues of simplexide

Abstract

Abstract Simplexides are natural glycolipids isolated from the marine sponge Plakortis simplex, and contain alkyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside. Simplexides can release of cytokines (IL-6) and chemokines (CXCL-8) from human monocytes and cause the expansion of natural killer T-cells (iNKTs) in vitro, with iNKTs contributing to the sustenance of immune homeostasis. Herein, the stereoselective syntheses of S-glycosidic analogues, i.e. S-simplexides, are described. The routes included Lewis acid promoted anomerisation of glycosyl thiols and thioglycolipids, as well as anomeric S-alkylation. Synthesis of O-glycosidic analogues are included. Heptadecanyl O- and S-glycosides as well as the 17-tritriacontyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside, a component of the natural simplexide isolate, all induced IL-6 and CXCL-8 production at both 10 and 30 μg/mL concentrations from PBMCs whereas the two S-simplexides were inactive. It is speculated that the lack of activity for the S-disaccharide analogue could be due to inhibition of cellular α-glucosidase, preventing degradation of the simplex disaccharide to a simpler galactopyranoside, whereas lack of activity for the S-galactolipid analogue could be due to increased conformational flexibility of S-glycosides. On the other hand, simpler unbranched O- and S-glycolipid analogues were active. Natural simplexide, and a synthetic simplexide, the 18-pentatriacontanyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside, were more potent than the new compounds tested.