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Synthesis of a β‐ d ‐Psicofuranosyl Sulfone and Inhibitory‐Activity Evaluation Against N ‐Acetylglucosaminyltransferase I
Author(s) -
Bella Maroš,
Yan Shi,
Šesták Sergej,
Kozmon Stanislav,
Lin ChunHung,
Mucha Ján,
Koóš Miroslav
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201701102
Subject(s) - chemistry , sulfone , stereochemistry , thio , aryl , alkyl , organic chemistry
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.