Synthesis and anti-HIV activity of 2-substituted 2'-deoxy-2'- fluoroadenosines
2-Iodo-6-methoxypurine 2'-deoxy-2'-fluororiboside 8 was prepared from 2- iodo-6-methoxypurine riboside 1 in 8 steps. Reaction of 8 with ammonia in methanol gave the 2-iodoadenosine derivative 9 in 69% yield. Treatment of 9 with various nucleophiles gave 2-substituted analogues of 2'-deoxy-2'- fluoroadenosine 10-12. 2'-Deoxy-2,2'-difluoroadenosine 14 was also prepared by the treatment of the quaternary salt 13 with fluoride ion, but similar reactions of 13 with chloride or bromide ion gave the corresponding piperidine congeners 15a,b.
Purine 2'-deoxy-2'-fluororibosides as antiinfluenza virus agents
Twenty purine 2'-deoxy-2'-fluororibosides were synthesized by enzymic pentosyl transfer from 2'-deoxy-2'-fluorouridine. Each nucleoside analogue was assayed for cytotoxicity in uninfected Madin-Darby canine kidney cells and for their ability to suppress influenza A virus infections in these cells. The most potent antivirial activity was observed with analogues having an amino group in the 2-position of the purine moiety. All 2-unsubstituted analogues were less potent than their 2-amino counterparts. Furthermore, 2- methyl, 2-methoxy, or 2-fluoro substitution obliterated antivirial activity. The most cytotoxic member of the series was the 2-fluoro-6-amino analogue (IC50 = 120 μM). 2'-Deoxy-2'-fluoroguanosine and those congeners readily converted to it by adenosine deaminase showed the most potent antivirial activity (IC50 = 15-23 μM). Little cytotoxicity was observed with this subgroup of analogues which renders them worthy of further investigation as potential antiinfluenza agents.
Tuttle,Tisdale,Krenitsky
p. 119 - 125
(2007/10/02)
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