Oligosaccharides Structurally Related to E-Selectin Ligands Are Inhibitors of Neural Cell Division: Synthesis, Conformational Analysis, and Biological Activity

• Published in: Journal of organic chemistry Vol. 60; no. 6; pp. 1502 - 1519
• Main Authors: Coteron, Jose M, Singh, Kamaljit, Asensio, Juan L, Dominguez-Dalda, Maria, Fernandez-Mayoralas, Alfonso, Jimenez-Barbero, Jesus, Martin-Lomas, Manuel, Nieto-Sampedro, Manuel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.03.1995; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; 3-DIMENSIONAL STRUCTURE; GROWTH-FACTOR RECEPTOR; H-1-NMR SPECTROSCOPY; ROTATING-FRAME NOE; METHYL BETA-LACTOSIDE; NMR-SPECTROSCOPY; MOLECULAR-DYNAMICS SIMULATIONS; MAGNETIC-RESONANCE SPECTROSCOPY; CONSISTENT FORCE-FIELD; CARBOHYDRATE-CHEMISTRY
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo00111a008

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 derivative 5) or the trisaccharide 3-fucosyllactose having N-acetylneuraminic and sulfate groups at the C-3; position of the galactose (3 and 4, respectively) have been synthesized and tested for the ability to inhibit the division of astrocytes and transformed cell lines and their conformation studied. Compounds 3 and Care structurally related to sulfated Lewis X and sialyl Lewis X which are known to be recognized by E-selectin. 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 efficiently prepared from methyl beta-lactoside. The conformational analysis has been carried out using NMR, molecular mechanics, and molecular dynamics. Compounds 2-4 were inhibitors in all cell types tested showing ID50 values in the mu M range; however, 5 showed a marked decrease in the ID50 value on astrocytes emphasizing upon the importance of the relative orientation of the fucosyl unit. Tetrasaccharide 3 was the most active on astrocytes (ID50 = 35 mu M), whereas the sulfate 4 was the best inhibitor on tumor-forming C6 glioma cells (ID50 = 79 mu M).