INHIBITORS OF GLYCOGEN-PHOSPHORYLASE-B - SYNTHESIS, BIOCHEMICAL SCREENING, AND MOLECULAR MODELING STUDIES OF NOVEL ANALOGS OF HYDANTOCIDIN

The synthesis and biochemical screening of four novel spironucleosides 1-4 against rabbit liver glycogen phosphorylase b (Gpb), along with m olecular 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 gene ral strategy for synthesis involved base-catalyzed condensation of die thyl 2,4-dioxoimidazolidine-5-phosphonate (5) with either 2-deoxy-D-ri bose or D-ribose. followed by sequential reactions involving ring-clos ure with phenylselenenyl chloride and reduction with tri-n-butyltin hy dride catalyzed by azobisisobutyronitrile. Compounds 2 and 4 were foun d to be weak competitive inhibitors of Gpb, whereas 1 and 3 were inact ive. (C) 1998 Elsevier Science Ltd. All rights reserved.