Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

Abstract

The identification of immunoactive agents for clinical and mechanistic applications is a very active area of research. In this vein, analogues of the potent immunostimulant KRN 7000 with diverse cytokine profiles have attracted considerable attention. Herein, we report on the synthesis and activity for four new C-glycosides of KRN 7000, 11-phenylundecanoyl and 11-p-fluorophenylundecanoyl derivatives of C-KRN 7000, 2,3-bis-epi-C-KRN 7000 and the reverse amide of C-KRN 7000. In mice, compared to C-KRN 7000, 2,3-bis-epi-C-KRN 7000 stimulated higher release of the anti-inflammatory cytokine IL-4 and lower release of the inflammatory cytokines IFN-γ and IL-12. The phenyl terminated alkanoyl and reverse amide analogues were inactive. These data suggest that structure activity effects for KRN 7000 are not necessarily additive and their use in the design of new analogues will require an improved understanding of how subtle structural changes impact on cytokine activity.

Synthetic preparation and immunological evaluation of β-mannosylceramide and related N-acyl analogues

“…This finding supports that obtained with the α-carba-GalCer series of compounds whereby the increased potency of certain fatty acyl analogues in the α-GalCer series did not transfer to the corresponding C-glycoside version. 41 As previously reported β-ManCer (2) could protect against lung metastasis but, mirroring the inactivity observed in the in vitro model, none of the N-acyl analogues tested showed any protection against tumour growth (Fig. 2).…”

Palladium catalyzed decarboxylative β-C-glycosylation of glycals with oxazol-5-(4H)-ones as acceptors

“…3 Studies have revealed that compared to O - or N -glycosidic linkages, the C -surrogates possess higher metabolic stability, thereby enhancing their physicochemical and pharmacological properties. 4 Indeed, the therapeutic uses of a large variety of C -glycoside natural products as well as drug candidates have been established, 5 including C -glycosyl amino acid analogues and the derived glycopeptides. 6…”