NOVEL, SPECIFIC NUCLEIC ACID CLEAVAGE AGENTS

IN THIS PHASE I STUDY WE WILL IMPROVE THE EFFICIENCY AND DEVELOP THE LINKING CHEMISTRY OF A NOVEL CLASS OF DNA CLEAVAGE REAGENTS. THESE AGENTS, WHICH UNDERGO THERMALLY TRIGGERED RADICAL FORMATION WILL BE MODIFIED WITH AN INTERCALATING GROUP IN ORDER TO INCREASE THE EFFICIENCY OF DNA CLEAVAGE. THE THERMAL CLEAVERS CAN BE PREPARED USING WELL ESTABLISHED SYNTHETIC ROUTES WHICH PROVIDE READY ACCESS TO A WIDE VARIETY OF DERIVATIVES. THE LENGTH OF THE LINKER ARM BETWEEN THE INTERCALATOR AND THE CLEAVER WILL BE OPTIMIZED WITH THE AID OF COMPUTER ASSISTED MOLECULAR DESIGN. EFFICIENCY OF CLEAVAGE WILL BE EXAMINED UNDER A VARIETY OF TEMPERATURES AND REACTION CONDITIONS. ANOTHER AIM OF THIS PHASE I STUDY IS TO PREPARE THERMALLY TRIGGERED CLEAVAGE AGENTS WITH ELECTROPHILIC GROUPS CAPABLE OF REACTION WITH NUCLEOPHILIC OLIGONUCLEOTIDES. THE REACTION OF THESE HIGHLY REACTIVE COMPOUNDS WITH MODEL NUCLEOPHILES WILL BE EXAMINED. THESE EXPERIMENTS CONSTITUTE A FEASIBILITY STUDY FOR THE DEVELOPMENT OF THE THERMALLY TRIGGERED CLEAVAGE AGENTS AS OLIGONUCLEOTIDE TARGETED AFFINITY CLEAVAGE AGENTS (PHASE II).