OLIGOSACCHARIDES STRUCTURALLY RELATED TO E-SELECTIN LIGANDS ARE INHIBITORS OF NEURAL CELL-DIVISION - SYNTHESIS, CONFORMATIONAL-ANALYSIS, AND BIOLOGICAL-ACTIVITY

Oligosaccharides containing either the Lewis X trisaccharide fragment (3-fucosyl-N-acetyllactosamine) with N-acetylgalactosamine at the C-3 position of the galactose unit (compound 2 and the 1,6-anhydro derivat ive 5) or the trisaccharide 3-fucosyllactose having N-acetylneuraminic and sulfate groups at the C-3; position of the galactose (3 and 4, re spectively) have been synthesized and tested for the ability to inhibi t the division of astrocytes and transformed cell lines and their conf ormation studied. Compounds 3 and Care structurally related to sulfate d Lewis X and sialyl Lewis X which are known to be recognized by E-sel ectin. The synthesis of 2 and 5 was accomplished by an original route starting from 1,6-anhydro-beta-D-mannose, while 3 and 4 were efficient ly prepared from methyl beta-lactoside. The conformational analysis ha s been carried out using NMR, molecular mechanics, and molecular dynam ics. Compounds 2-4 were inhibitors in all cell types tested showing ID 50 values in the mu M range; however, 5 showed a marked decrease in th e ID50 value on astrocytes emphasizing upon the importance of the rela tive orientation of the fucosyl unit. Tetrasaccharide 3 was the most a ctive on astrocytes (ID50 = 35 mu M), whereas the sulfate 4 was the be st inhibitor on tumor-forming C6 glioma cells (ID50 = 79 mu M).