Synthesis of 5-Thio-α-GalCer Analogues with Fluorinated Acyl Chain on Lipid Residue and Their Biological Evaluation

Abstract

Invariant natural killer T (iNKT) cells are a subclass of T cells that initiates the secretion of T helper 1 and 2 cytokines after recognizing CD1d protein presented glycolipid antigens. In this Letter, we designed and synthesized a novel series of CD1d ligand α-galactosylceramides (α-GalCers) in which the acyl chain backbone of the lipid was incorporated with fluorine atoms. The in vivo evaluation of immunostimulatory activities revealed that the synthesized α-5-thio-galactopyranosyl-N-perfluorooctanoyl phytosphingosine exhibited a remarkable potency toward selectively enhancing T H 1 cytokine production with the IFN γ/IL-4 ratio of 9/1, while its perfluorotetradecanoyl counterpart showed T H 2 profile with an IFN γ/IL-4 ratio of 0.59/1. The analogues synthesized here would be used as probes to study lipid−protein interactions in α-GalCer/CD1d complexes.

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“…Zhu and Doherty with others focused on synthesis and biological tests of thioglycoside analogues of αGalCer (α-S-GalCer), providing an α-S-GalCer analogue of 6-O-glucosylated with a biased Th1-type profile. , Du and others synthesized a series of 5-Thio-α-GalCer with fluorinated acyl chains or normal acyl chains. The significant cytokine type change of that high IFN-γ/IL-4 secretion was achieved by α-5-thio-galactopyranosyl-N-perfluorooctanoyl phytosphingosine. , Cerundolo and others synthesized and improved the iNKT activating ability of the nonglycosidic compound threitolceramide (ThrCer) . Calenbergh’s team modified αGalCer analogues with C4″-, C5′′-, C6′′, and phytosphingosine modification, that improved the iNKT cell stimulating ability in vitro and in vivo. − Park’s group recently synthesized α-fluorocarbonyl-modified αGalCer analogues through an alkyne–alkyne cross coupling strategy.…”

“…The significant cytokine type change of that high IFN-γ/IL-4 secretion was achieved by α-5thio-galactopyranosyl-N-perfluorooctanoyl phytosphingosine. 211,212 threitolceramide (ThrCer). 213 Calenbergh's team modified αGalCer analogues with C4″-, C5′′-, C6′′, and phytosphingosine modification, that improved the iNKT cell stimulating ability in vitro and in vivo.…”

Chemical Biology of αGalCer: A Chemist's Toolbox for the Stimulation of Invariant Natural Killer T (iNKT) Cells

“…Subsequent truncation of the acyl chain in 5-S-αGalCer and 5-S-PBS-25 resulted in flattened IL-4 release, which prompted the same research group to further explore the cytokine secretion profile with additional acyl chain modifications, particularly focusing on the incorpo- ration of fluorine atoms and a strong T H 1 biasingactivity in mouse in vivo experiments was observed with the perfluorooctanoyl acyl moiety in 47. [149] While iminosugar analogs were found to be inactive, aminocyclitol analog HS44 promoted iNKT cell expansion in vitro, although with a lower potency than KRN7000, and the production of a slightly T H 2 biased response. [150]…”

“…Conversion of 52 to 48 was afforded after dehydrobromination, ester reduction, benzylation, dihydroxylation, and finally regioselective benzylation through formation of the corresponding stannylene acetal (Scheme 5B). Further exploring modifications of the pyranose ring, 5‐ S ‐KRN7000 (Figure 7), in which the ring oxygen is substituted by a sulfur atom, was first synthesized by the group of Du [149] and found to better stimulate iNKT cells to produce T H 1 cytokines in murine in vitro and in vivo experiments. Subsequent truncation of the acyl chain in 5‐ S ‐αGalCer and 5‐ S ‐PBS‐25 resulted in flattened IL‐4 release, which prompted the same research group to further explore the cytokine secretion profile with additional acyl chain modifications, particularly focusing on the incorporation of fluorine atoms and a strong T H 1 biasingactivity in mouse in vivo experiments was observed with the perfluorooctanoyl acyl moiety in 47 [149] .…”

Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

“…An endocyclic- S -containing derivative of α-GalCer (KRN7000) was synthesized for use as an adjuvant, and was observed to have a stronger immunostimulatory effect on IFN-γ production in invariant natural killer T cells as compared to its endocyclic- O -containing counterpart [74]. In combination with perfluoroalkyl lipid modification, a selective modulation of the immune response could be achieved where the glycomimetic 5-thio-α-galactopyranosyl- N -perfluorooctanoyl phytosphingosine was shown to selectively stimulate T H 1 cytokine production, while its perfluorotetradecanoyl derivative elicited a T H 2 cytokine profile.…”