title: Carbohydrate transition state mimics: synthesis of imidazolo-pyrrolidinoses as potential nectrisine surrogates.
abstract: The syntheses of four glyco-imidazoles, which are pentose-derivatives belonging to the D-series, as well as the syntheses of their L-enantiomers, are reported. Starting from the known linear xylo, lyxo, arabino, and ribo imidazolo-pentoses in both the L- and the D-series, intramolecular Walden inversion led to the corresponding arabino, ribo, xylo, and lyxo pyrrolidinopentoses in the D- and the L-series, respectively, protection and deprotection steps being unavoidable prerequisites. The structures and configurations of all eight pyrrolidinopentoses were determined unambiguously, by a combination of 1H/13C NMR spectroscopy, circular dichroism and [alpha](D) values, in conjunction with single-crystal X-ray diffraction analysis of the L-xylo stereoisomer. Examination of the inhibitory properties of these imidazolo-pyrrolidinoses against six commonly encountered glycosidases led to the conclusion that by and large the L-stereoisomers are inactive, whereas three out the four D-stereoisomers proved to be poor to moderate inhibitors. It appears therefore that the most basic N(1) atom is not located in an optimal topology to be protonated easily inside the enzyme's active site.
authors.affiliation: Ecole Nationale Supérieure de Chimie, Université de Haute-Alsace, 3, rue Alfred Werner, F-68093, Mulhouse, France.
authors.forename: Théophile
authors.initials: T
authors.lastname: Tschamber
authors.forename: François
authors.initials: F
authors.lastname: Gessier
authors.forename: Estelle
authors.initials: E
authors.lastname: Dubost
authors.forename: Jeffery
authors.initials: J
authors.lastname: Newsome
authors.forename: Céline
authors.initials: C
authors.lastname: Tarnus
authors.forename: Josiane
authors.initials: J
authors.lastname: Kohler
authors.forename: Markus
authors.initials: M
authors.lastname: Neuburger
authors.forename: Jacques
authors.initials: J
authors.lastname: Streith
mesh_terms: D001089:Arabinose / Q000138:chemical synthesis; D002241:Carbohydrates / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000378:metabolism*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D050113:Imino Furanoses; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry*; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry; D012266:Ribose / Q000138:chemical synthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002241:Carbohydrates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D050113:Imino Furanoses; D011759:Pyrrolidines; D011760:Pyrrolidinones; C055825:nectrisine; D012266:Ribose; D001089:Arabinose; D006026:Glycoside Hydrolases