Synthesis of 1,1-linked galactosyl mannosides carrying a thiazine ring as mimetics of sialyl Lewis X antigen: investigation of the effect of carboxyl group orientation on P-selectin inhibition.
This paper describes the synthesis of 1,1-linked galactosyl mannosides as sialyl Lewis X mimetics that contain a spiro-ring to position the carboxylate group in a well-defined orientation. It was found that compound 4 is more active as a P-selectin inhibitor (IC50 = 19 microM) than the parent disaccharide 2, which contains a flexible carboxyl group (IC50 = 193 microM). This result is consistent with that observed in the previous NMR study of sialyl Lewis X bound to P-selectin. The chemistry described here should be useful for the development of selective inhibitors of E-, P-, and L-selectins.
Shibata
K
K
Frontier Research Program, Institute of Physical and Chemical Research (RIKEN), Saitama, Japan.
Hiruma
K
K
Kanie
O
O
Wong
C H
CH
D002240:Carbohydrate Sequence; D009682:Magnetic Resonance Spectroscopy; D008362:Mannosides / Q000138:chemical synthesis*; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000138:chemical synthesis*; D019007:P-Selectin / Q000737:chemistry*; D011134:Polysaccharides / Q000138:chemical synthesis*; D000080506:Sialyl Lewis X Antigen; D013843:Thiazines / Q000138:chemical synthesis*
D008362:Mannosides; D009844:Oligosaccharides; D019007:P-Selectin; D011134:Polysaccharides; D000080506:Sialyl Lewis X Antigen; D013843:Thiazines