Glucose-based spiro-heterocycles as potent inhibitors of glycogen phosphorylase.
Glucopyranosylidene-spiro-1,4,2-oxathiazoles were prepared in high yields by NBS-mediated spiro-cyclization of the corresponding glucosyl-hydroximothioates. In an effort to synthesize analogous glucopyranosylidene-spiro-1,2,4-oxadiazolines, with a nitrogen atom instead of the sulphur, attempted cyclizations resulted in aromatization of the heterocycle with opening of the pyranosyl ring. Enzymatic measurements showed that some of the glucose-based inhibitors were active in the micromolar range. The 2-naphthyl-substituted 1,4,2-oxathiazole displayed the best inhibition against RMGPb (K(i)=160 nM), among glucose-based inhibitors known to date.
Nagy
Veronika
V
Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary.
Benltifa
Mahmoud
M
Vidal
Sébastien
S
Berzsényi
Eszter
E
Teilhet
Cathie
C
Czifrák
Katalin
K
Batta
Gyula
G
Docsa
Tibor
T
Gergely
Pál
P
Somsák
László
L
Praly
Jean-Pierre
JP
D000818:Animals; D005947:Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D011817:Rabbits; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D013844:Thiazoles; C540068:glucopyranosylidene-spiro-oxathiazole; D024982:Glycogen Phosphorylase, Muscle Form; D005947:Glucose