Synthesis and structure-activity relationships of 6-substituted 2',3'-dideoxypurine nucleosides as potential anti-human immunodeficiency virus agents

Abstract

In order to study the structure-activity relationships of 2'',3''-dideoxypurine nucleosides as potential anti-HIV agents, various 6-substituted purine analogues have been synthesized and examined in virus-infected and uninfected human peripheral blood mononuclear cells. N6-methyl-2'',3''-dideoxyadenosine (D2MeA, 7a) was initially synthesized from adenosine via 2'',3''-O-bisxanthate 3. As extension of this reaction to other N6-substituted compounds failed, a total synthetic method utilizing 2'',3''-dideoxyribose derivative 9 was used for the synthesis of other purine nucleosides. An acid-stable derivative of N6-methyl-2'',3''-dideoxyadenosine, 2''-fluoroarabinofuranosyl analogue 32 (D2MeFa), has been synthesized from the appropriate carbohydrate 24 by condensation with N6-methyladenine 23. Among these compounds, N6-methyl derivative (D2MeA) 7a proved to be one of the most potent antiviral agents. The order of potency for the 6-substituted compounds was NHMe> NH2 > Cl .apprxeq. N(Me)2 > SMe > OH .apprxeq. NHEt > SH > NHBn .apprxeq. H. The results suggest that a bulk tolerance effect at the 6-position of the 2'',3''-dideoxypurine nucleoside may dictate the antiviral activity of these compounds. Acid-stable analogue 32 (D2MeFA) was found to be 20-fold less potent than the parent compound. Both D2MeA and D2MeFA were resistant to calf intestine adenosine deaminase. The presence of a fluorine atom in the carbohydrate moiety greatly increased stability to acid, making D2MeFa a potential orally active antiviral agent that could be useful for the treatment of retroviral infections in humans.