Inhibitors of glycogen phosphorylase b: synthesis, biochemical screening, and molecular modeling studies of novel analogues of hydantocidin.
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.
Agasimundin
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Department of Chemistry and Biochemistry, University of Maryland, Baltimore County 21250, USA.
Mumper
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Hosmane
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D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000201:enzymology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010763:Phosphorylase b / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006827:Hydantoins; D008024:Ligands; D009705:Nucleosides; D013141:Spiro Compounds; C068815:hydantocidin; D010763:Phosphorylase b