OPTICAL RESOLUTION IN THE INOSITOLPHOSPHATE SERIES

THE OVERALL OBJECTIVE OF THIS STUDY IS TO DEVELOP A SIMPLE, GENERAL, AND PRACTICAL METHOD FOR RESOLVING DERIVATIVES OF DL-MYO-INOSITOL INTO D- AND L-ENANTIOMERS. A NOVEL APPROACHBASED ON PUTATIVE ENANTIOSELECTIVE HYDROLYSIS CATALYZED BY HYDROLASE ENZYMES IS SUGGESTED. THE PURE ENANTIOMERS ARE REQUIRED AS KEY SYNTHONS FOR THE PREPARATION OF D-MYO-INOSITOL-1,4,5-TRISPHOSPHATE, THE MYO-INOSITOL-1-PHOSPHONO-6-GLYCANS, AND OTHER COMPOUNDS RELATED TO THESE INTRACELLULAR SECOND-MESSENGER MOLECULES AND FOR THE SYNTHESIS OF ANALOGS AS POTENTIAL THERAPEUTIC AGENTS. THE PHASE I PROGRAM IS DESIGNED TO ESTABLISH THE FEASIBILITYOF THE GENERAL APPROACH. FOR THIS, THE HYDROLYSIS OF SELECTED DL-MYO-INOSITOL ESTERS AS MODEL SUBSTRATES, CATALYZED BY A NUMBER OF HYDROLASE ENZYMES, WILL BE STUDIED TO DETERMINE RELATIONSHIPS BETWEEN STRUCTURAL FEATURES AND ESTERASE ACTIVITY, WITH EMPHASIS ON SYNTHONS FOR THE PREPARATION OF D-MYO-INOSITOL-1-PHOSPHATES. DURING PHASE II, THE GENERAL APPROACH WILL BE EXTENDED AND APPLIED TO THE PREPARATION OF OTHER MEMBERS OF THE PHOSPHOINOSITOL SERIES DERIVED FROM THE PHOSPHATIDYLINOSITOL METABOLIC CYCLE AND TO THE DESIGN, SYNTHESIS, AND EVALUATION OF THEIR STRUCTURAL AND BIOCHEMICAL ANALOGS.