9-β-D-2′,3′-dideoxyribonucleosides of four N(6)-substituted purines and 1-deazapurine were prepared using crude nucleoside N-deoxyribosyltransferases (EC 2.4.2.6) from Lactobacillus leichmannii. The 2′,3′-dideoxynucleosides derived from N(6)-substituted purines (1–4) are inhibitors of the replication of human immunodeficiency virus type 1 (HIV-1), with EC90 values in the range 20–100 and 20–200 μm, depending on the cell line used, and have low in vitro toxicity at their effective concentrations.
References
1.
BalzariniJ., and BroderS. (1988) Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. In: Clinical Use of Antiviral Drugs (ed. De ClercqE.), pp. 361–385. Martinus Nijhoff Publishing, Boston.
2.
BartonD.H.R., and SubramanianR. (1977) Reactions of relevance to the chemistry of aminoglycoside antibiotics. Part 7. Conversion of thiocarbonates into deoxysugars. J Chem Soc Perkin Trans1: 1718–1723.
3.
BetbederD., and HutchinsonD.W. (1990) The enzymatic synthesis of 1-β-D-2′-deoxyribofuranosyl imidazoles. Nucleosides Nucleotides9: 569–577.
4.
BetbederD.HutchinsonD.W., and RichardsA. O'L. (1989) The stereospecific enzymatic synthesis of 9-β-D-2′-deoxyribofuranosyl-1-deazapurine. Nucleic Acids Res17: 4217–4222.
5.
CarsonD.A., and WassonD.B. (1988) Synthesis of 2′,3′-dideoxynucleosides by enzymatic trans-glycosylation. Biochem Biophys Res Commun155: 829–834.
6.
ChuC.K.SchinaziR.F.ArnoldB.H.CannonD.L.DoboszewskiB.BhadtiV.B., and GuZ. (1988) Comparative activity of 2′,3′-saturated and unsaturated pyrimidine and purine nucleosides against human immunodeficiency virus type 1 in peripheral blood mononuclear cells. Biochem Pharmacol37: 3543–3548.
7.
DahlbergJ.E.MitsuyaH.BlamS.B.BroderS., and AaronsonS.A. (1987) Broad spectrum antiretroviral activity of 2′,3′-dideoxynucleosides. Proc Natl Acad Sci USA84: 2469–2473.
8.
KoszalkaG.W., and KrenitskyT.A. (1986) Process for the preparation of therapeutic nucleosides. Euro Pat Appl 0206497 A2.
9.
KoszalkaG.W.KrenitskyT.A.RideoutJ.L., and BurnsC.L. (1988) Therapeutic nucleosides. Euro Pat Appl 0286425 A2.
10.
LinT.-S.SchinaziR., and PrusoffW.H. (1987) Potent and selective in vitro activity of 3′-deoxythymidin-2′-ene (3′-deoxy-2′,3′-didehydrothymidine) against human immunodeficiency virus in vitro. Biochem Pharmacol36: 2713–2718.
11.
MitsuyaK.WeinholdK.J.FurmanP.A.St ClairM.H.LehrmanS.N.GalloR.L.BolognesiD.P.BarryD.W., and BroderS. (1985) 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA82: 7096–7100.
12.
PauwelsR.BalzariniJ.BabaM.SnoeckR.ScholsD.HerdewijnP.DesmeyterJ., and De ClercqE. (1988) Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Meth20: 309–321.
13.
RichmanD.D.FischlM.A.GriecoM.H.GottliebM.S.VolberdingP.A.LaskinO.L.LeedomJ.L.GroopmanJ.E.MildvanD.HirschM.S.JacksonG.G.DurackD.T., and Nusinoff-LehrmanS. (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. New England J Med317: 192–197.
14.
RobinsR.K., and ChristensenB.E. (1952) The chlorination of certain purinones with phosphorus oxychloride in the presence of aliphatic tertiary amines. J Am Chem Soc74: 3624–3627.
15.
RussellA.F.GreenbergS., and MoffattJ.G. (1973) Reactions of 2-acyloxyisobutyryl halides with nucleosides. II. Reactions of adenosine. J Am Chem Soc95: 4025–4030.
16.
ShiraeH.KobayashiK.ShiragamiH.IrieY.YasudaN., and YokozekiK. (1989) Production of 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine from 2′,3′-dideoxyuridine and the corresponding purine bases by resting cells of Escherichia coli AJ 2595. App; Environ Microbiol55: 419–424.
17.
ShiragamiH.IrieY.ShiraeH.YokozekiK., and YasudaN. (1988) Synthesis of 2′,3′-dideoxyuridine via deoxygenation of 2′,3′-O-(methoxymethylene)uridine. J Org Chem53: 5270–5173.