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Design of Glycosyltransferase Inhibitors: Pyridine as a Pyrophosphate Surrogate
Author(s) -
Wang Shuai,
CuestaSeijo Jose A.,
Lafont Dominique,
Palcic Monica M.,
Vidal Sébastien
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201301871
Subject(s) - chemistry , stereochemistry , pyridine , pyrophosphate , glycosyltransferase , uridine diphosphate , azide , amide , active site , enzyme , moiety , combinatorial chemistry , nucleoside , biochemistry , organic chemistry
A series of ten glycosyltransferase inhibitors has been designed and synthesized by using pyridine as a pyrophosphate surrogate. The series was prepared by conjugation of carbohydrate, pyridine, and nucleoside building blocks by using a combination of glycosylation, the Staudinger–Vilarrasa amide‐bond formation, and azide–alkyne click chemistry. The compounds were evaluated as inhibitors of five metal‐dependent galactosyltransferases. Crystallographic analyses of three inhibitors complexed in the active site of one of the enzymes confirmed that the pyridine moiety chelates the Mn 2+ ion causing a slight displacement (2 Å) from its original position. The carbohydrate head group occupies a different position than in the natural uridine diphosphate (UDP)–Gal substrate with little interaction with the enzyme.