SYNTHESIS AND BIOLOGICAL EVALUATION OF ENDOCYCLIC 2′,3′-DIDEHYDRO- 2′,3′-DIDEOXYMETHANOCARBA ADENOSINE

ABSTRACT

This is the first report describing the synthesis and conformation of methanocarba nucleosides incorporating an endo (β-face) cyclopropyl at the 2′,3′ position of 2′,3′-didehydro-2′,3′-dideoxy carbocyclic nucleosides. These nucleoside isosteres have been shown to exist in a unique extreme eastern conformation. This prediction was confirmed by x-ray crystallography and high resolution NMR spectroscopy. As expected, the methanocarba adenosine compound was neither a substrate nor an inhibitor of adenosine deaminase. However, some of the compounds synthesized demonstrated moderate antiviral activity against HSV-1. The methanocarba adenosine and its triphosphate form were evaluated as inhibitors of HIV-1 reverse transcriptase.

ACKNOWLEDGMENTS

The adenosine deaminase assay and the in vitro antiviral assays were performed by Jay Brownell in our laboratory at the University of Minnesota. The testing against HIV-1 was performed by Southern Research Institute in Frederick, Maryland. The assay for HIV reverse transcriptase enzyme recognition was performed by Lucile White at Southern Research Institute in Birmingham, Alabama. Data collection and structure solution were conducted by Victor Young and William W. Brennessel at the X-Ray Crystallographic Laboratory, 160 Koltoff Hall, Chemistry Department, University of Minnesota. Some of the intermediates were also synthesized by Lakshmi Akella in our laboratory at the University of Minnesota.