C-Glucosylated malonitrile as a key intermediate towards carbohydrate-based glycogen phosphorylase inhibitors.
Glycogen utilization involves glycogen phosphorylase, an enzyme which appears to be a potential target for the regulation of glycaemia, as the liver isoform is a major player for hepatic glucose output. A single C-glucosylated malonitrile allowed for the synthesis of three glucose-based derivatives namely bis-oxadiazoles, bis-amides and a C-glucosylated tetrahydropyrimidin-2-one. When evaluated as glycogen phosphorylase inhibitors, two of the synthesized compounds displayed inhibition in the sub-millimolar range. In silico studies revealed that only one out of the bis-amides obtained and the C-glucosylated tetrahydropyrimidin-2-one may bind at the catalytic site.
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.
Sophie
S
Feuillastre
Aikaterini S
AS
Chajistamatiou
Constantinos
C
Potamitis
Maria
M
Zervou
Panagiotis
P
Zoumpoulakis
Evangelia D
ED
Chrysina
Jean-Pierre
JP
Praly
Sébastien
S
Vidal
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002241:Carbohydrates / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D006031:Glycosylation; D008958:Models, Molecular; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000201:enzymology; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D009570:Nitriles; C000945:dicyanmethane; D024982:Glycogen Phosphorylase, Muscle Form