Design, synthesis, and biological evaluation of novel KRN7000 analogues using 5α-gem-difluorocarba-β-l-arabinopyranose

Abstract

Two novel KRN7000 analogues, where d-galactopyranosyl residue was replaced by 5α-gem-difluorocarba-β-l-arabinopyranose, were designed based on docking computation and energy decomposition analyses. The target compounds were synthesized employing the key steps of Ferrier's carbocyclic ring closure and gem-difluoride formation with d-galactose as starting material. The in vivo bioassay revealed that the designed glycolipids could stimulate iNKT cells to produce cytokines IFN-γ and IL-4. The introduced hydroxyl groups on glycolipid acyl chain provided extra CD1d substrate affinities, and thus favored to boost Th1-type cytokine secretion. When the ring oxygen was replaced by CF₂ group on sugar unit, its TCR affinities were enhanced in contrast with KRN7000. The in vivo cytokine profiles induced by synthetic glycolipids were initially dominated by the binding ability of CD1/glycolipid, and then adjusted by affinity toward TCR in CD1/α-GalCer/TCR triplex structure. The current results could be helpful in designing of more efficient α-GalCer analogs.