Synthesis and evaluation of amino-modified alpha-GalCer analogues

Abstract

Alpha-GalCer analogues featuring a phytoceramide 3- and 4-amino group have been synthesized. A Mitsunobu reaction involving phthalimide was employed for the introduction of the amino groups at the 3- and 4-positions of suitable phytosphingosine-derived precursors. The influence of these modifications on the interaction with the T-cell receptor of NKT cells was investigated, as well as the capacity of the amino-modified analogues to induce a cytokine response after in vivo administration.

Figure 1

Structures of KRN7000 (1) and amino-modified analogues (2–5).

Figure 2

INF-γ and IL-4 secretion after intraperitoneal injection of α-GalCer (1) and 2–5 in mice (* P < 0.01 vs α-GalCer).

Scheme 1

Synthesis of the 3-amino-3-deoxy-α-GalCer analogues 2 and 3

Scheme 2

Synthesis of the D-ribo and L-lyxo glycosidation acceptors 22 and 23

Scheme 3

Synthesis of the 4-amino-4-deoxy-α-GalCer analogues 4 and 5