Synthesis and evaluation of L-Rhamnose 1C-Phosphonates as nucleotidylyltransferase inhibitors

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DOIResolve DOI: http://doi.org/10.1021/jo401542s
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TypeArticle
Journal titleThe Journal of Organic Chemistry
ISSN0022-3263
1520-6904
Volume78
Issue19
Pages98229833; # of pages: 12
AbstractWe report the synthesis of a series of phosphonates and ketosephosphonates possessing an l-rhamnose scaffold with varying degrees of fluorination. These compounds were evaluated as potential inhibitors of α-d-glucose 1-phosphate thymidylyltransferase (Cps2L), the first enzyme in Streptococcus pneumoniae l-rhamnose biosynthesis, and a novel antibiotic target. Enzyme–substrate and enzyme–inhibitor binding experiments were performed using water-ligand observed binding via gradient spectroscopy (WaterLOGSY) NMR for known sugar nucleotide substrates and selected phosphonate analogues. IC50 values were measured and Ki values were calculated for inhibitors. New insights were gained into the binding promiscuity of enzymes within the prokaryotic l-rhamnose biosynthetic pathway (Cps2L, RmlB–D) and into the mechanism of inhibition for the most potent inhibitor in the series, l-rhamnose 1C-phosphonate.
Publication date
PublisherACS Publications
LanguageEnglish
AffiliationNational Research Council Canada; Aquatic and Crop Resource Development
Peer reviewedYes
NRC number55823
NPARC number21268658
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Record identifierd9f6c1ac-fb26-44cf-a378-3c1d2f186d05
Record created2013-11-06
Record modified2016-05-09
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