Synthesis and anti-HIV activity of various 2'- and 3'-substituted 2',3'-dideoxyadenosines: a structure-activity analysis

Abstract

A systematic synthesis was undertaken of 2'',3''-dideoxyadenosine analogues with either an azido, fluorine, or hydroxyl group substituted in the "up" or "down" position of C-2 or C-3 of the sugar moiety. The compounds were evaluated against the cytopathogenicity of human immunodeficiency virus (HIV) for MT-4 cells. The four azido derivatives 6, 7, 8, and 9 were synthesized by a nucleophilic displacement reaction with lithium azide on the mesylates 3, 2, 5, and 4. (Diethylamido)sulfur trifluoride was used for the synthesis of 10-12. The compound 13 was obtained by 2''-deoxygenation of 9-(3-fluoro-3-deoxy-.beta.-D-xylofuranosyl)adenine. Among the azido derivatives, compound 8 with the 3''-azido "down" was slightly more active than 2'',3''-dideoxyadenosine (1) but considerably more toxic, and, of the fluorine series, compound 11, with the 2''-fluoro "up", was the most selective inhibitor of HIV, although it was less active than 1. Hence, none of the newly synthesized compounds proved more selective in their anti-HIV activity than the parent compound, 1.