Inhibitors of glycogen phosphorylase b : synthesis, biochemical screening, and molecular modeling studies of novel analogues of hydantocidin

• Published in: Bioorganic & medicinal chemistry Vol. 6; no. 7; pp. 911 - 923
• Main Authors: Agasimundin, Yankanagouda S., Mumper, Mary W., Hosmane, Ramachandra S.
• Format: Journal Article
• Language: English
• Published: England 01.07.1998
• Subjects: Animals; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Hydantoins - chemical synthesis; Hydantoins - chemistry; Hydantoins - metabolism; Hydantoins - pharmacology; Ligands; Models, Molecular; Muscle, Skeletal - enzymology; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - metabolism; Nucleosides - pharmacology; Phosphorylase b - antagonists & inhibitors; Phosphorylase b - metabolism; Protein Binding; Rabbits; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - metabolism; Spiro Compounds - pharmacology
• ISSN: 0968-0896
• DOI: 10.1016/S0968-0896(98)00055-8

The synthesis and biochemical screening of four novel spironucleosides 1-4 against rabbit liver glycogen phosphorylase b (Gpb), along with molecular modeling studies on compound 2 and its 4-hydroxy analogue VII, have been presented. Gpb is a key enzyme of glycogen metabolism, and is known to be involved in the control of diabetes mellitus. The general strategy for synthesis involved base-catalyzed condensation of diethyl 2,4-dioxoimidazolidine-5-phosphonate (5) with either 2-deoxy-D-ribose or D-ribose, followed by sequential reactions involving ring-closure with phenylselenenyl chloride and reduction with tri-n-butyltin hydride catalyzed by azobisisobutyronitrile. Compounds 2 and 4 were found to be weak competitive inhibitors of Gpb, whereas 1 and 3 were inactive.