Carbohydrate transition state mimics: synthesis of imidazolo-pyrrolidinoses as potential nectrisine surrogates.
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.
Tschamber
Théophile
T
Ecole Nationale Supérieure de Chimie, Université de Haute-Alsace, 3, rue Alfred Werner, F-68093, Mulhouse, France.
Gessier
François
F
Dubost
Estelle
E
Newsome
Jeffery
J
Tarnus
Céline
C
Kohler
Josiane
J
Neuburger
Markus
M
Streith
Jacques
J
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
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D050113:Imino Furanoses; D011759:Pyrrolidines; D011760:Pyrrolidinones; C055825:nectrisine; D012266:Ribose; D001089:Arabinose; D006026:Glycoside Hydrolases