Glucan-like synthetic oligosaccharides: iterative synthesis of linear oligo-β-(1,3)-glucans and immunostimulatory effects

Abstract

Small reducing and linear oligo-beta-(1,3)-glucans, which are able to act as phytoallexin elicitors or as immunostimulating agents in anticancer therapy, were synthesized according to an iterative strategy that involved a unique key monosaccharidic donor. To avoid anomeric mixtures, the reducing entity of the target oligomers was first locked with benzyl alcohol and further selective deprotection of the 3-OH with DDQ afforded the desired building block as an acceptor. The latter was then used in a second cycle of glycosylation/deprotection to afford the desired disaccharide, and successive reiterations of this process provided the desired oligomers. Unusual conformational behaviors were observed by standard NMR sequences and supported by NOESY studies. Finally, removal of protecting groups afforded free tri-, tetra-, and pentaglucosides in good overall yields. Two oligosaccharides representing linear laminaritetraose and laminaripentaose were compared to the recently described beta-(1,3)-glucan phycarine. Following an intraperitoneal injection, the influx of monocytes and granulocytes into the blood and macrophages into the peritoneal cavity was comparable to that caused by phycarine. Similarly, both oligosaccharides stimulated phagocytic activity of granulocytes and macrophages. Using ELISA, we also demonstrated a significant stimulation of secretion of IL-1beta. Together these results suggest that the synthetic oligosaccharides have similar stimulatory effects as natural beta-(1,3)-glucans.

β-Glucans, History, and the Present: Immunomodulatory Aspects and Mechanisms of Action

“…Considerable heterogeneity of all natural β-glucans, not only from saccharomycetes but also from other sources, obviously was and continues to be the cause of a series of mutually contradicting conclusions. Recently, an attempt was made to solve this problem using semisynthetic and synthetic probes, suitable for accurate immunological research (Jamois et al, 2005).…”

ANTI-STRESS ACTION OF SEVERAL ORALLY-GIVEN Β-Glucans

“…This considerable heterogeneity of all natural β-glucans, continues to be the cause of a series of mutually contradicting conclusions. Recently, an attempt was made to solve this problem using semisynthetic and synthetic probes suitable for accurate immunological research 9 . In addition, very few studies comparing various commercially available glucans exist 10,11 .…”

How to Improve Chemical Synthesis of Laminaribiose on a Large Scale

“…While acetyl groups at O-2 on the donor species are expected to stabilize intermediate oxonium, to induce nucleophilic attack on the opposite site and consequently to favor 1,2-trans couplings, these desired results could not be easily attained using glucopyranosyl acceptors characterized by a free 3-OH and acyl groups to protect other hydroxyl functions [15]. However this difficulty could be overcome by using acceptors bearing a 4,6-benzylidene group [16,17]. Nevertheless, we thought that such elaborated compounds could not be suitable for a pre-industrial process because they require too many syntheses and purification steps for molecule having non-pharmaceutical uses.…”