title: Sugar derivatives as new 6-phosphogluconate dehydrogenase inhibitors selective for the parasite Trypanosoma brucei.
abstract: Sugar derivatives mimicking compounds which take part in the catalysed reaction have been assayed as alternative substrates and/or competitive inhibitors of 6-phosphogluconate dehydrogenase from Trypanosoma brucei and sheep liver. Phosphonate analogues have been synthesised and the new compound 5-deoxy-5-phosphono-D-arabinonate shows good selectivity towards the parasite enzyme. A number of 4-carbon and 5-carbon aldonates are strong inhibitors of the parasite enzyme with K(i) values below the substrate K(m) and some acyl derivatives are also potent inhibitors. At least five of the compounds showing a significant selectivity for the parasite enzyme represent leads for trypanocidal drugs against this recently validated target.
authors.affiliation: Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Via L. Borsari 46, 44100, Ferrara, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pasti
authors.forename: Eliana
authors.initials: E
authors.lastname: Rinaldi
authors.forename: Carlo
authors.initials: C
authors.lastname: Cervellati
authors.forename: Franco
authors.initials: F
authors.lastname: Dallocchio
authors.forename: Renaud
authors.initials: R
authors.lastname: Hardré
authors.forename: Laurent
authors.initials: L
authors.lastname: Salmon
authors.forename: Stefania
authors.initials: S
authors.lastname: Hanau
mesh_terms: D000818:Animals; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000378:metabolism; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
chemical_list: D002241:Carbohydrates; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D010734:Phosphogluconate Dehydrogenase