Synthesis of Unprecedented Sulfonylated Phosphono‐exo‐Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes |
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| Authors: | Christophe J.‐M. Frédéric Dr. Abdellatif Tikad Jian Fu Dr. Weidong Pan Ruixiang B. Zheng Dr. Akihiko Koizumi Dr. Xiaochao Xue Prof. Todd L. Lowary Prof. Stéphane P. Vincent |
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| Affiliation: | 1. University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, Namur, Belgium;2. The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, P. R. China;3. Department of Chemistry and Alberta Glycomics Centre, University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, Canada;4. (+32)?81‐72‐45‐17 0000-0001-6258-9058 University of Namur (UNamur), Département de Chimie, Laboratoire de Chimie Bio-Organique, Namur, Belgium |
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| Abstract: | 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, GlfT1, and GlfT2, the three mycobacterial galactofuranose processing enzymes. Molecule 46‐(E) is the first characterized inhibitor of GlfT1 reported to date and was also found to efficiently inhibit UGM in a reversible manner. Interestingly, GlfT2 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. |
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| Keywords: | glycals glycosyltransferase phosphonates sulfones tuberculosis |
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