Synthetic analogs of sialyl Lewis x

Sammanfattning: The sialyl Lewis x (SLex) tetrasaccharide is the smallest recognizable ligand for selectins. The selectins constitute a vital part of the inflammatory cascade for recruitment of leukocytes to a site of tissue damage or microbial infection. If too many leukocytes are recruited, normal, not injured, cells can be damaged; a process known from chronic inflammatory diseases such as reumatoid arthritis, psoriasis, and from septic shock and reperfusion damage. Sialyl Lewis x saccharides were originally identified as human tumor-associated antigens and are found on all highly malignant types of cancer cells. The identification of the SLex tetrasaccharide and later synthetic efforts have elucidated the biologically important features of the molecule. A large number of analogs and mimics have been designed in order to get simpler and more stable compounds for use as anti-inflammatory drugs. Sialic acid-containing oligosaccharides, such as sialyl Lewis x, can form lactones under slightly acidic conditions. These lactones are generally more immunogenic due to their increased rigidity and it has been proposed that the lactones are the actual immunogens. The lactones are however not hydrolytically stable and are therefore difficult to investigate and to raise antibodies against. Lactams were introduced as analogs to lactones and were found to be structurally similar and more stable against hydrolysis. Lactam analogs of a number of monosialylated gangliosides (GM2, GM3, GM4) were synthesized and used with success. This thesis describes the synthesis of the sialyl Lewis x tetrasaccharide, the Lewis x trisaccharide, the 1’’’-2’-, 1’’’-4’-lactam- and 2-acetamido analogs of the sialyl Lewis x tetrasaccharide, the 2- and 4-acetamido- and 2- and 4-lactam analogs of the Lewis x trisaccharide. The key-steps in the syntheses were regio- and stereoselective galactosylations of one common monosaccharide diol acceptor, stereoselective fucosylation and regio- and stereoselective sialylations to yield the oligosaccharidic products in 10-62% over-all yield from monosaccharidic starting materials.