Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues. (18th April 2017)

• Record Type: Journal Article
• Authors: Altiti, Ahmad S.; Ma, Xiaojing; Zhang, Lixing; Ban, Yi; Franck, Richard W.; Mootoo, David R.
• Is Part Of: Carbohydrate research. Volume 443/444(2017)
• Page Start: 73
• Page End: 77
• Publication Date: 2017-04-18
• Subjects: Glycolipid -- CD1d -- NKT -- Cytokine -- C-glycoside; Carbohydrates -- Periodicals; Chemistry, Organic -- Periodicals; Biochemistry -- Periodicals; Carbohydrates -- Periodicals; Chimie organique -- Périodiques; Glucides -- Périodiques; Biochemistry; Carbohydrates; Chemistry, Organic; Periodicals; Electronic journals; 507.78
• DOI: 10.1016/j.carres.2017.03.005
• Languages: English
• ISSNs: 0008-6215

Abstract

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. These compounds have been shown to activate iNKT cells via presentation by CD1d. 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. Graphical abstract: Highlights: C-glycosides of KRN 7000 with novel ceramide segments were prepared. The 2, 3-bisepimer of C -KRN 7000 showed a lower Th-1 cytokine bias than C-KRN 7000. 11-Phenyl undecanoic acid amides and the inverse amide of C-KRN 7000 were inactive. Structure activity effects for KRN 7000 are not necessarily additive.