3-fluoro- and 3,3-difluoro-3,4-dideoxy-KRN7000 analogues as new potent immunostimulator agents: total synthesis and biological evaluation in human invariant natural killer T cells and mice.

We propose here the synthesis and biological evaluation of 3,4-dideoxy-GalCer derivatives. The absence of the 3- and 4-hydroxyls on the sphingoid base is combined with the introduction of mono or difluoro substituent at C3 (analogues 8 and 9, respectively) to evaluate their effect on the stability of the ternary CD1d/GalCer/TCR complex which strongly modulate the immune responses. Biological evaluations were performed in vitro on human cells and in vivo in mice and results discussed with support of modeling studies.

Synthesis and Biological Evaluation of 4'-,3'--Propylene-Linked Bicyclic Nucleosides.

A set of pyrimidine nucleosides fused with a 4'-,3'--propylene bridge was successfully synthesised in 12 steps from 1,2:5,6-di--isopropylidene-α-d-glucofuranose, an inexpensive starting material, based on a ring-closing metathesis (RCM) reaction followed by Vorbrüggen-type nucleobase coupling. Antiviral and cytotoxicity activities of the targeted modified nucleosides, as well as their phosphoramidate prodrugs, are described.

Focus on the controversial activation of human iNKT cells by 4-deoxy analogue of KRN7000.

4-Deoxy-alpha-GalCer analogues are considered weaker agonists than KRN7000 for the stimulation of human iNKT cells, but this remains strongly debated. In this work, we described a strategy toward 4-deoxy-alpha-GalCers with, as a key step, a metathesis reaction allowing sphingosine modifications from a single ethylenic alpha-galactoside precursor. The 4-deoxy-KRN7000 derivative 2, described here, induced potent cytokinic responses, comparable to those of KRN7000, both from human iNKT cells in vitro and from their murine counterpart in vivo.