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Synthesis of Unprecedented Sulfonylated Phosphono‐ exo ‐Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes
Author(s) -
Frédéric Christophe J.M.,
Tikad Abdellatif,
Fu Jian,
Pan Weidong,
Zheng Ruixiang B.,
Koizumi Akihiko,
Xue Xiaochao,
Lowary Todd L.,
Vincent Stéphane P.
Publication year - 2016
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.201603161
Subject(s) - furanose , chemistry , stereochemistry , pyranose , phosphonate , enzyme , uridine , biochemistry , organic chemistry , ring (chemistry) , rna , gene
This study reports a new methodology to synthesize exo ‐glycals bearing both a sulfone and a phosphonate. This synthetic strategy provides a way to generate exo ‐glycals displaying two electron‐withdrawing groups and was applied to eight different carbohydrates from the furanose and pyranose series. The Z / E configurations of these tetrasubstituted enol ethers could be ascertained using NMR spectroscopic techniques. Deprotection of an exo ‐glycal followed by an UMP (uridine monophosphate) coupling generated two new UDP (uridine diphosphate)‐galactofuranose analogues. These two Z / E isomers were evaluated as inhibitors of UGM, Gl f T1, and Gl f T2, the three mycobacterial galactofuranose processing enzymes. Molecule 46‐( E ) is the first characterized inhibitor of Gl f T1 reported to date and was also found to efficiently inhibit UGM in a reversible manner. Interestingly, Gl f T2 showed a better affinity for the ( Z ) isomer. The three enzymes studied in the present work are not only interesting because, mechanistically, they are still the topic of intense investigations, but also because they constitute very important targets for the development of novel antimycobacterial agents.