A series of 5′-amido derivatives of 5-(2″-thienyl)-2′,3′,5′-β-trideoxyuridine were prepared. The compounds were tested for their inhibition of cellular DNA polymerase α and α HIV-RT. The succinic fumaric and maleic acid derivatives of 5-(2″-thienyl)-2′,3′,5′-β-trideoxyuridine were investigated. None of the compounds inhibited HIV-RT. The fumaric acid derivative inhibited DNA pol α with IC50 33 μg ml−1. The succinic acid derivative was about half as active with IC50 76 μg ml−1. The 5′-N-acyl derivatives also were structurally compared to the monomethyl ester of the triphosphate using the Sybyl program.
AdachiT.YamadaY., and InoueI. (1977) An alternative method for the selective reduction of unsaturated nucleoside azides to the amine. Synthesis: 45–46.
2.
AdamsR., and UlichL.H. (1920) The use of oxalyl chloride and bromide for producing acid chloride, acid bromides or acid anhydrides. III. J Am Chem Soc42: 599–611.
3.
AggarwalS.K.GoguS.R.RanganS.R.S., and AgrawalK.C. (1990) Synthesis and biological evaluation of prodrugs of zidovudine. J Med Chem33:1505–1510.
4.
AsakuraJ.-L., and RobinsM. J. (1988) Cerium (IV) catalyzed iodination at C5 of uracil nucleosides. Terahedron Lett29: 2855–2858.
5.
BalzariniJ.CooneyD.A.DalaiM.KangG.-J.CuppJ.E.De ClercqE.BroderS., and JohnsD.G. (1987) 2′, 3′-Dideoxycytidine: Regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleoside synthesis. Mol Pharmacol32: 798–806.
6.
BjörsneM.ClassonB.KvarnströmI., and SamuelssonB. (1993) Synthesis of mimics to thymidine triphosphate and 3′-Deoxy-3′-Fluorothymidine triphosphate. Nucleosides & Nucleotides12: 529–536.
7.
ChuC.K.BhadtiV.S.DoboszewskiB.GuZ.P.KosugiY.PullaiahK.C., and Van RoeyP. (1989) General synthesis of 2′, 3′-Dideoxynucleosides and 2′, 3′-Didehydro-2′, 3′-dideoxynucleosides. J Org Chem54: 2217–2225.
8.
DaviesJ.F.IIAlmassyR.J.HostomskaZ.FerreR.A., and HostomskyZ.(1994) 2.3 Å crystal structure of catalytic domain of DNA polymerase β. Cell76:1123–1133.
9.
EvansP.R.FarrantsG.W., and HudsonP.J. (1981) Phosphofructokinase: Structure and control. Phil Trans R Soc LondB 293: 53–62.
GronowitzS.WesterlundC., and HörnfeldtA.-B., (1975) The synthetic utility of heteroaromatic azido compounds. I. Preparation and reduction of some 3-Azido-2-substituted furans, thiophenes, and selenophenes. Acta Chem ScandB 29: 224–232.
12.
HaradaK.Matulic-AdamicJ.PriceR.W.SchinaziR.F.WatanabeK.A., and FoxJ. (1987) Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5′-modified analogous of 2′-fluoroarabinosylpyrimidine nucleosides. J Med Chem30: 226–229.
13.
HeifetzA.KeenanR.W., and ElbornA.D. (1979) Mechanism of Action of Tunicamycin on the UDP-GlcNAc: Dollchyl-Phosphate GlcNAc-l-Phosphate Transferase. Biochemistry18: 2186–2192.
14.
HeninY.GouyetteC.SchwartzO.DebouzyJ.C.NeumannJ.-M., and Huynh-DinhT. (1991) Lipophilic glycosyl phosphotriester derivatives of AZT: Synthesis, NMR trans-membrane transport study, and antiviral activity. J Med Chem34: 1830–1837.
15.
HennT. F. G.GarnettM. C.ChhabraS.R.BycroftB.W., and BaldwinR. W. (1993), Synthesis of 2′-Deoxyuridine and 5-Fluoro-2′-deoxyuridine derivatives and evaluation in antibody targeting studies. J Med Chem36:1570–1579.
16.
Jacob-MolinaA., and ArnoldE. (1991) HIV reverse transcriptase structure-function relationships. Biochem30: 6351–6361.
17.
Jacob-MolinaA.DingJ.NanniR.G.ClarkA.D.Jr.LuX.TantilloC.WilliamsR.L.KamerG.FerrisA.L.ClarkP.HiziA.HughesS.H., and ArnoldE. (1993), Crystal structure of Human Immunodeficiency Virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proc Natl Acad Sci USA90: 6320–6324.
18.
JohanssonN.-G. (1993), Structure, antiviral activity, and chemistry of acyclic nucleoside analogues. Advances in antiviral drug design. Rega Institute for Medicinal Research Katholieke Universiteit Leuven, Belgium, JAI Press Inc.87–177.
19.
JohanssonN.G.MalmbergH.C.G.NoreenR.SahlbergS.C.SohnD.D., and GronowitzS. (1990) PCT Int. Appl. WO 8912 061. Chem Abstr112: 235778e:
20.
JohnsonM.A., and FridlandA. (1989) Phosphorylation of 2′, 3′-Dideoxyinosine by cytosolic 5′-Nucleotidase of human lymphoid cells. Mol Pharmacol36: 291–295.
21.
KohlstaedtLA.WangJ.FriedmanJ.M.RiceP.A., and SteitzT.A. (1992) Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science256: 1783–1790.
22.
McGuiganC.JonesB.C.N.TollerfieldS.M., and RileyP.A. (1992) Synthesis and biological evaluation of haloalkyl phosphonate triester derivatives of araA and araC. Antiviral Chem Chemother3: 79–94.
23.
McGuiganC.PathiranaR.N.BalzariniJ., and De ClerqE. (1993a) Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT. J Med Chem36: 1048–1052.
24.
McGuiganC.PathiranaR.N.BalzariniJ., and De ClerqE. (1993b) Phosphoramidate derivatives of AZT as inhibitors of HIV: Studies on the carboxyl terminus. Antiviral Chem Chemother4: 97–101.
25.
McGuiganC.TurnerS.NichollsS.R.O'ConnorT.J., and KinchingtonD. (1994) Haloalkyl phosphate derivatives of AZT as inhibitors of HIV: Studies in the phosphate region. Antiviral Chem Chemother5: 162–168.
26.
OllisD.L.BrickP.HamlinR.XuongN.G., and SteitzT.A. (1985) Structure of large fragment of Escherichia coli DNA polymerase 1 complexed with dTMP. Nature313: 762–766.
27.
OtoskiR.M., and WilcoxC.S. (1988) An approach to lipophilic nucleotide phosphate analogues. Synthesis of a lipophilic isostere of ATP. Tetrahedron Lett29: 2615–2618.
28.
PannecouckeX.ParmentierG.SchmittG.DolleF., and LuuB. (1994) Synthesis of the phosphodiester of 3β (7β-Hydroxycholesterol) and of 5′-(3′-Deoxy-3′-azidothymidine). Tetrahedron50:1173–1178.
29.
PelletierH.SawayaM.R.KumarA.WilsonS.H., and KrautJ. (1994) Structures of tertinary complexes of rat DNA polymerase β, a DNA template primer, and ddCTP. Science264:1891–1903.
30.
PerssonT.HörnfeldtA.-B.GronowitzS., and JohanssonN.G. (1994) Thienyl-substituted nucleosides and their triphosphates. Antiviral Chem Chemother5: 395–402.
31.
SamanoM.C., and RobinsM.J. (1991) Efficent reduction of azides to amines with tributylstannane. High-yield synthesis of amino and diamino deoxynucleosides. Tetrahedron Lett.32: 6293–6296.
32.
SandströmE., and ÖbergB. (1993) Antiviral therapy in Human Immunodeficiency Virus infections. Drugs45: 488–508.
33.
SawayaM.R.PelletierH.KumarA.WilsonS.H., and KrautJ. (1994) Crystal structure of rat DNA polymerase β: Evidence for a common polymerase mechanism. Science264:1930–1935.
34.
SchinaziR.F. (1993) Competetive inhibitors of Human Immunodeficiency Virus reverse transcriptase. Perspect Drug Discovery Des1:151–180.
35.
SchoeneckerJ.W.TakemoriA.E., and PortogheseP.S. (1986) Irreversible blockage of opioid types by ester homologues of β-funaltrexamine. J Med Chem29:1868–1871.
36.
SergheraertC.PierlotC.TartarA.HeninY., and LemaitreM. (1993) Synthesis and anti-HIV evaluation of D4T and D4T 5′-monophosphate prodrugs. J Med Chem36: 826–830.
37.
SharmaA.P.OllapallyA.P., and LeeH.J. (1993) Synthesis and anti-HIV activity of prodrugs of azidothymidine. Antiviral Chem Chemother4: 93–96.
38.
StarnesM.C., and ChengY.-C. (1987) Cellular metabolism of 2′, 3′-Dideoxycytidine, a compound active against Human Immunodeficiency Virus in vitro. J Biol Chem262: 988–991.
39.
StarretJ.E.TortolaniD.R.BakerD.C.OmarM.T.HebblerA.K.WosJ.A.MartinJ.C., and MansuriM.M. (1990) The use of acetyl bromide for the multigram synthesis of the anti-HIV agent 2′-, 3′-Didehydro-2′, 3′-Dideoxycytidine (d4C). Nucleosides & Nucleotides9: 885–897.
40.
SteitzT.A. (1993), DNA- and RNA-dependent DNA polymerases. Curr Opin Struct Biol3: 31–38.
41.
SteitzT.A.BeeseL.FreemontP.S.FriedmanJ.M., and SandersonM.R. (1987) Structual studies of klenow fragment: An enzyme with two active sites. ColdSpring Harbor Symposia on Quantitative BiologyL11: 465–471.
42.
SuhadolnikR.J. (1990), Nucleosides as Biological Probes. New York; Wiley.
43.
ZhangH.VrangL.UngeT., and ÖbergB. (1993) Characterization of HIV reverse trancriptases with Tyr181- > Cys and Leu 100- > lle mutations. Antiviral Chem Chemother4: 1–8.
