Selectin antagonists : synthesis and conformational comparison of C- and O-glycosidic tetrasaccharide mimetics related to sialyl Lewis*

Abstract

Numerous disease states can be traced back to an excessive or uncontrolled leukocyte accumulation to sites of inflammation or tissue injury. This recruitment of leukocytes, under normal conditions a vital defense mechanism against invading pathogens, is mediated by the interaction of the selectins with their physiological carbohydrate determinant sLex (3) as binding epitope of the natural selectin ligands. SLex (3) served as lead structure in the development of selectin antagonists, which have been considered as a promising therapeutic approach against these diseases. C-glycosidic structures play a prominent role in developing hydrolytically stable mimetics as well as in understanding conformational issues relevant for the binding process. C-glycosidic sLex mimetics 81a and 82 were designed to investigate the influence of the exoanomeric effect on the conformational stability and the biological activity of these tetrasaccharide mimetics. Flexibility of target compound 81a should be enhanced due to the lacking exo-anomeric effect around the C-glycosidic linkage. Implementation of steric constraints as the methyl group in compound 82 should proof the hypothesis, that the missing exo-anomeric effect can be compensated by steric factors. Furthermore, comparison of binding affinity should allow a quantification of the entropy contribution to the inhibitory potential caused by the exo-anomeric effect. We successfully developed a synthesis for the target tetrasaccharide mimetics 81a and 82 based on the Giese radical addition of an anomeric fucosyl radical to the electron deficient double bond of an enone system. Conformational investigation of the target molecules revealed the possibility to compensate for the loss of the exo-anomeric effect by the introduction of sterically demanding substituents next to the C-glycosidic linkage. The influence of the 20-30% larger distance of H-5Fuc and H-2Gal in compound 82 compared to Oglycosidic mimic 33 on biological activity has to be proven by current investigation.