Minimum structure requirement of immunomodulatory glycolipids for predominant Th2 cytokine induction and the discovery of non-linear phytosphingosine analogs

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

“…60) The analogs of one aromatic group at the sphingosine chain also activated NKT cells, 35,40,57,58,60,61) while the introduction of two aromatic groups at both the sphingosine and the acyl chains of 1 diminished its immunostimulatory activities, as confirmed by Park et al…”

“…To connect a galactose part in -orientation, researchers have used 1-OH free garactopyranose (D), 30,33,44) thiogalactoside (E), 28,30,36,37,41) galactosyl trichloroacetimidate (F), [27][28][29][32][33][34]36,39,43) phosphite (G), 33) phosphate (H), 42) acetate (I), 37) or halide (J) as the galactose donor. 4,25,26,29,31,35,38,40) Hague, 31) and trichloroacetimidate (L) with trimethylsilyl triflate (60%) reported by Kimura et al, 32) gave the highest -stereoselectivity (exclusivity). Next, how do we constract the phytosphingosine part possessing the four functional groups with exact chiralities at high diastereo-and enantiomeric purity?…”

“…After the disclosure of the structure 1 by Kirin Brewery, 4) many reports on the synthesis of 1 were published from 1995 to 2011, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] including practical synthesis of it by Kirin group. 25) As shown in Fig.…”

“…3), an analog of 1 with truncated alkyl chains, the sphingosine chain especially was drastically shortened, from C 18 to C 9 , causing NKT cells to produce IL-4, one of the major Th2-type cytokines, predominantly in mice in vivo. 35,[46][47][48] In addition, synthesis of the C-glycoside of OCH (3) was achieved by Toba et al, but detailed biological information on it was not reported. 49) In 2004, Oki et al suggested that production of IFN-by NKT cells requires a longer stimulation period through TCR than for IL-4 production.…”

“…52) The correlation between the chain length of the lipid part of 1 and Th1/Th2 cytokine balance produced by NKT cells was examined by Savage and co-workers in 2004, 53) and also by researchers at Daiichi Asubio Pharma Co., in 2007, independently. 35) Recently, Kim and co-workers found that an analog of 1 with a diheptylamino group at the end of the C 8 acyl chain (KBC-007, 5) induced enhanced but biased IL-4 production in mice in vitro. 54) In addition, their dinonylamino analog (KBC-009, 6) exhibited a useful adjuvant effect through NKT cell activation when it was co-administrated with a nasal influenza vaccine.…”