SYNTHETIC ANALOGS OF FRUCTOSE PHOSPHATES AND RIBOSIDES

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The main objective of this project is the synthesis of a carbocyclic analog of the important metabolic regulator 2,6-diphosphofructose. This molecule is the strongest known positive effector of the enzyme 6-phosphofructokinase which catalyzes a key control step in the breakdown of glucose or glucagon to provide ATP. The carbocyclic analog is hypothesized to be much more stable than the parent regulator and may well be inert to an enzyme which normally hydrolyzes 2,6-diphosphofructose, 2,6-diphosphofructo-2-phosphatase (FBPase 2). The availability of this analog will allow several interesting experiments to be carried out and these experiments will lead to an increased understanding of the reactions catalyzed by phosphofructokinase and 2,6-diphosphofrucoto-2-phosphatase. More speculatively, if the analog does mimic the stimulatory effect of 2,6-diphosphofructose and is stable and inert to FBPase 2, then it may be of use in the treatment of disorders involving glucose metabolism. Carbocyclic analogs of ribosides, including 5-phosphoribosyl-1-pyrophosphate and 5-phosphoribosylamine will be prepared. These molecules are substrates for enzymes active in the synthesis of purine nucleotides and these analogs may be of use as antivial agents. This project will develop a new process for the synthesis of carbocyclic analogs of carbohydrates. The process can be applied in any are where analogs of carbohydrates or glycosides are desired. For example, carbocyclic analogs of glycoside containing antibiotics can be prepared based on this new technology and will be inert to glycosidase enzymes. Finally, a bis-carba analog of AMP will be prepared. This molecule is of interest because it may be able to replace natural AMP in enzymic processes but will be much more robust than the natural molecule. A very stable analog of AMP could find wide application in industrial processes which require ATP for use with immobilized or modified enzymes.