Semisynthesis of fuscoside B analogues and eunicosides, and analysis of anti-inflammatory activity

Abstract

A small library of semisynthetic analogues of fuscol and eunicol have been prepared and evaluated for in vivo topical anti-inflammatory activity using the mouse-ear edema assay. The first glycosylation of fuscol and eunicol has been achieved using a modified Koenigs–Knorr glycosylation to synthesize new fuscosides and eunicosides, a novel structural class of diterpene glycosides. The availability of adequate glycosylation methods for this synthesis was limited owing to the instability of the glycosyl acceptors. Glycosyl donor protecting group type had a pronounced effect on overall glycosylation yields of a model glycosyl acceptor. This synthesis provided access to the unnatural β-glycosides allowing for an evaluation of the effect of differing anomeric stereochemistry on anti-inflammatory activity. The PEGylated derivatives of fuscol and eunicol were also synthesized by a convenient acid-promoted solvolysis of the natural product aglycones. This work highlights the importance of the glycan portion of fuscoside B, notably the stereochemical configuration of the glycosidic linkage, in the observed anti-inflammatory activity.