title: Synthesis and evaluation of l-rhamnose 1C-phosphonates as nucleotidylyltransferase inhibitors.
abstract: We 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.
authors.affiliation: Department of Chemistry, Dalhousie University , 6274 Coberg Road, P.O. Box 15,000, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Loranger
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Forget
authors.forename: Nicole E
authors.initials: NE
authors.lastname: McCormick
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Syvitski
authors.forename: David L
authors.initials: DL
authors.lastname: Jakeman
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D009711:Nucleotides / Q000737:chemistry*; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D063065:Organophosphonates / Q000737:chemistry*; D012210:Rhamnose / Q000138:chemical synthesis* / Q000737:chemistry*; D013296:Streptococcus pneumoniae / Q000737:chemistry* / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D009711:Nucleotides; D063065:Organophosphonates; D009713:Nucleotidyltransferases; C020587:glucose-1-phosphate thymidylyltransferase; D012210:Rhamnose