RESUMO
Several N-acylglucosamine derivatives of sialyl Lewis X (1-3) were prepared using a combined chemical enzymatic approach and evaluated as an inhibitor of E-selectin-mediated cellular adhesion. Compounds with aromatic functionality, 1 and 2, were found to be 3-10 times more potent than the N-acetyl derivative (14) in an ELISA E-selectin cell adhesion assay. Conformational analysis with NMR indicated that the sialyl Lewis x domain of 1 retained the conformation of the N-acetyl derivative (14) despite the presence of the N-naphthamido group. The dramatic order of magnitude increase in potency of these monovalent structures can be utilized to design more potent selectin-based cell adhesion inhibitors.
Assuntos
Adesão Celular/efeitos dos fármacos , Selectina E/metabolismo , Glucosamina/metabolismo , Oligossacarídeos/metabolismo , Oligossacarídeos/farmacologia , Sítios de Ligação , Configuração de Carboidratos , Sequência de Carboidratos , Células HL-60 , Humanos , Antígenos do Grupo Sanguíneo de Lewis , Ligantes , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Oligossacarídeos/química , Antígeno Sialil Lewis XRESUMO
The development and execution of the first examples of a new and general approach to carbocyclic analogs of carbohydrates ("pseudo-sugars") is presented. Complete experimental details for the preparation of the carbocyclic analog of beta-D-fructofuranose 6-phosphate are described for the first time. In the conclusion, the success of the synthetic strategy is analyzed and an approach to retrosynthetic analysis based on "unitive synthons" is offered for consideration.