Synthesis and structure-activity relationships of C-glycosylated oxadiazoles as inhibitors of glycogen phosphorylase.
A series of per-O-benzoylated 5-beta-D-glucopyranosyl-2-substituted-1,3,4-oxadiazoles was prepared by acylation of the corresponding 5-(beta-D-glucopyranosyl)tetrazole. As an alternative, oxidation of 2,6-anhydro-aldose benzoylhydrazones by iodobenzene I,I-diacetate afforded the same oxadiazoles. 1,3-Dipolar cycloaddition of nitrile oxides to per-O-benzoylated beta-D-glucopyranosyl cyanide gave the corresponding 5-beta-D-glucopyranosyl-3-substituted-1,2,4-oxadiazoles. The O-benzoyl protecting groups were removed by base-catalyzed transesterification. The 1,3,4-oxadiazoles were practically inefficient as inhibitors of rabbit muscle glycogen phosphorylase b while the 1,2,4-oxadiazoles displayed inhibitory activities in the micromolar range. The best inhibitors were the 5-beta-D-glucopyranosyl-3-(4-methylphenyl- and -2-naphthyl)-1,2,4-oxadiazoles (K(i)=8.8 and 11.6 microM, respectively). A detailed analysis of the structure-activity relationships is presented.
Tóth
Marietta
M
Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary.
Kun
Sándor
S
Bokor
Eva
E
Benltifa
Mahmoud
M
Tallec
Gaylord
G
Vidal
Sébastien
S
Docsa
Tibor
T
Gergely
Pál
P
Somsák
László
L
Praly
Jean-Pierre
JP
D000818:Animals; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006031:Glycosylation; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011817:Rabbits; D013329:Structure-Activity Relationship
D010069:Oxadiazoles; D024982:Glycogen Phosphorylase, Muscle Form