This research will develop metabolically stable antiviral and antitumor methylphosphonate analogs of 2',5'-oligo(A) n, where n = 3. The inhibitor of protein synthesis in interferon-treated cells has been identified as the 5' triphosphate of adenosyl(2'-5')-adenosine, commonly known as 2',5'oligo(A)3. This inhibition is due to the activation of a 2',5'-oligo(A)-dependent endonuclease, which degrades viral MRNA. Unfortunately, 2',5'-oligo(A) is rapidly degraded in the cell by the endonucleases, making the inhibition of protein synthesis only a transient effect. Nuclease-resistant methylphosphonate analogs of 5'triphosphate of 2',5'-oligo(A) would constitute metabolically stable analogs that would be potentially potent antiviral agents. The nonionic characteristics of methylphosphonate analogs will make such analogs cell permeable, thus possessing an added advantage over the highly charged 2',5'oligo(A). The 5' dephosphorylated 2',5'-oligo(A) has been reported to inhibit cell DNA synthesis, but it is limited in its effects by the instability of the compound. The synthesis of a cell-permeable, nuclease-resistant methylphosphonate analog of 5'OH (2',5')-oligo(A) could potentially lead to a potent antitumor drug. With the successful synthesis of these compounds in Phase I, the Phase II program will involve studying the efficacy and toxicity of these compounds.
Anticipated Results:Potent antiviral and antitumor agents with less harmful side effects will have tremendous commercial applications. These compounds will be used in the treatment of viral and neoplastic diseases.National Cancer Institute
