Synthesis of a β-D-Psicofuranosyl Sulfone and Inhibitory-Activity Evaluation Against N-Acetylglucosaminyltransferase I

摘要

Alkyl or aryl 3-acetamido-3-deoxy-2-thio-β-D-psicofuranosides bearing a phosphate group at C-1, which were originally designed as potential GnT-I inhibitors (GnT = N-acetylglucosaminyltransferase) by computational methods, were found to be unstable. Therefore their structure was slightly modified to stable 3-acetamido-3-deoxy-β-D-psicofuranosyl sulfones. A model inhibitor of GnT-I, namely ethyl 3-acetamido- 3-deoxy-1-O-phosphono-β-D-psicofuranosyl sulfone, was synthesized based on the transformation of D-mannose into 3-azido-3-deoxy-D-psicofuranose as the key intermediate. Thioglycosylation of 1,2-O-diisopropylidene-protected 3-azido- or 3- amino-3-deoxy-D-psicofuranose derivatives with thiols in the presence of BF_3·OEt_2 was found to be a crucial step in the synthesis of the predicted inhibitor. Biochemical evaluation of the proposed inhibitor revealed only a very weak inhibition of GnT-I. Additional molecular modeling showed that further modifications of the UDP-mimicking part of the synthesized inhibitor are necessary to improve its inhibitory activity against GnT-I.