Development of LPS antagonistic therapeutics: synthesis and evaluation of glucopyranoside-spacer-amino acid motifs

Sepsis is a serious medical condition characterized by bacterial infection and a subsequent massive systemic inflammatory response. The release of proinflammatory products and mediators from responding innate immune cells, such as mononuclear phagocytes, directly contributes to the pathogenesis of sepsis. The primary bacterial trigger of inflammation is lipopolysaccharide (LPS), which interacts with the germline-encoded macrophage receptor cluster of differentiation 14 (CD14) via its Lipid A moiety. In an effort to identify compounds that block LPS-induced inflammation we investigated a series of Lipid A analogs that lack a disaccharide core yet still possess potent antagonistic activity against LPS. We found it beneficial to develop molecules that contain the following: a glucopyranoside core, hydrophobic ether substituents, and an amino acid to provide an ionic character to the constructs. Here we report an efficient synthesis of molecules of this type and the ensuing biological studies thereof.