Synthesis and immunostimulatory activity of diethanolamine-containing lipid A mimics

Toll-like receptor (TLR) 4 plays important roles in the innate immunity and the development of adaptive immune responses. TLR4 ligands that can modulate the TLR4-mediated signalling pathways therefore have great potential for therapeutic applications. In this paper, we describe the synthesis of three lipid A mimics (2-4) as potential TLR4 ligands, in which a diethanolamine moiety is employed to replace the reducing end (D-glucosamine) of the archetypical lipid A disaccharide structure. Biological studies indicate that the lipid A mimic with six acyl chains (2) exhibits potent immune stimulatory activity in that it induces a significant increase in the ICAM-1 expression of human pre-monocytic THP-1 cells, as well as significant production of the cytokines TNF-alpha, IL-6, and IL-1 beta. The mimic with eight acyl chains (3) is inactive towards both the induction of ICAM-1 expression, and the cytokines TNF-alpha, and IL-6, yet induces significant production of IL-1 beta when tested at higher concentration. Finally, the lipid A mimic 4, a derivative of 2, that contains an additional 1-hydroxybutyl group as a result of an unexpected ring opening reaction of a tetrahydrofuran molecule, is active in all respects tested, albeit with reduced potency. These data suggest that diethanolamine-containing lipid A mimics can be potent immune stimulating agents.