Cardiovascular and central nervous system ischemia are major medical problems which remain largely untreatable. Therapies targeting (I) adenosine, a known cytoprotective compound during conditions of ischemia, and (ii) oxygen- derived free radicals have shown strong promise in both cardiovascular and central nervous system ischemia. Adenosine receptor agonists have proven to be not practical because they produce side effects and lack the ability to reduce free radical production. On the other hand, inhibition of adenosine deaminase (ADA) by (+)-EHNA ((+)-erythro-9- (2(S)-hydroxy-3-(R)-nonyl)adenine) is one possibility that addresses both targets and provides fewer side effects due to greater selectivity in ischemic tissue. Current syntheses of (+)-EHNA, being lengthy and/or employing expensive starting materials, are not practical on a large scale. An economical synthesis is a prerequisite for preparing the material necessary for extensive clinical studies and commercial drug production. In the proposed project, it will be elaborated a short and efficient route to derivatives of 9'-OH-(+)-EHNA, a functionalized analogue of (+)-EHNA. A number of these analogues will be synthesized and determined their inhibitory power in ADA assays. In addition adenosone release assay will be performed and IC50 of cellular ADA inhibition will be determined.
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