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 greater than NH2 greater than Cl approximately N(Me)2 greater than SMe greater than
OH approximately NHEt greater than SH greater than NHBn approximately 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.