A series of new AZT conjugates with alkyl and oxyalkyl ether phospholipids was synthesized and evaluated for inhibitory activities against HIV-1 and HIV-2. The alkoxyethyl derivatives 6a-c proved 3- to 5-fold more active against HIV-1 and HIV-2 than the alkyl analogues 6d-f. A trend for higher activity with longer alkyl side-chains was observed. However, the analogues with the shortest chain possessed the most favourable therapeutic index.
BabaM.PauwelsR.HerdewijnP.De ClercqE.DesmyterJ., and VandeputteM. (1987) 2′,3′-Dideoxythymidine and its 2′,3′-unsaturated derivatives are potent and selective inhibitors of HIV replication in vitro. Biochem Biophys Res Commus142: 128–134.
2.
BalzariniJ.KangG.-J.DalaiM.HerdewijnP.De ClercqE.BroderS., and JohnsD.G. (1987) The anti-HTLV-lll (anti-HIV) and cytotoxic activity of 2′,3′-didehydro-2′,3′-dideoxyribonucleosides. A comparison with their parental 2′-3′-dideoxyribonucleosides. Mol Pharmacol32: 162–167.
3.
BalzariniJ.BabaM.PauwelsR.HerdewijnP., and De ClercqE. (1988) Antiretrovirus activity of 3′-fluoro- and 3′-azido-substituted pyrimidine 2′,3′-dideoxynucleoside analogues. Biochem Pharmacol37: 2847–2856.
4.
BalzariniJ.HerdewijnP., and De ClercqE. (1989) Differential patterns of intracellular metabolism of 2′,3′-didehydro-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. J Biol Chem264: 6127–6133.
5.
BalzariniJ.NaesensL.SlackmuyldersJ.NiphuisH.RosenbergI.HolyA.SchellekensH., and De ClercqE. (1991) 9-(2-Phosphonyl-methoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection of rhesus monkeys. AIDS5: 21–28.
6.
BaumannW.J.SchmidH.O.UlshöferH.W., and MangoldH.K. (1967) Alkoxylipids IV. Synthesis and characterization of naturally occurring ethers, esters and ether esters of diols. Biochim Biophys Acta144: 355–365.
7.
ChattopadhyayaJ.B., and ReeseC.B. (1979) Some observations relating to phosphorylation methods in oligonucleotide synthesis. Tetrahedron Letters52: 5059–5062.
8.
FurmanP.A.FyfeJ.A.St. ClairM.H.WeinholdK.RideoutJ.L.FreemanG.A.Nusinoff LehrmanS.BolognesiD.P.BroderS.MitsuyaH., and BarryD.W. (1986) Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA83: 8333–8337.
9.
HaoZ.CooneyD.A.HartmanN.R.PernoC.F.FridlandA.De VicoL.SarngadharanM.G.BroderS., and JohnsD.G. (1988) Factors determining the activity of 2′-3′dide-oxynucleosides in suppressing human immunodeficiency virus in vitro. Mol Pharmacol34: 431–435.
10.
HeninY.GouyetteC.SchwartzO.DebouzyJ.-C.NeumannJ.-M., and Huynh-DinhT. (1991) Lipophilic glycosyl phosphotriester derivatives of AZT: synthesis, NMR transmembrane transport study, and antiviral activity. J Med Chem34: 1830–1837.
11.
HerdewijnP.BalzariniJ.De ClercqE.PauwelsR.BabaM.BroderS., and VanderhaegheH. (1987) 3′-Substituted 2′,3′-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J Med Chem30: 1270–1278.
12.
HostetlerK.Y.RichmanD.D.CarsonD.A.StuhmillerL.M.van WijkG.M.T., and van den BoschH. (1992) Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3′ deoxythymidine diphosphate dimyristoylglycerol a lipid prodrug of 3′ deoxythymidine. Antimicrob Agents Chemother36: 2025–2029.
13.
HostetlerK.Y.ParkerS.SridharC.N.MartinM.J.LiJ.-L.StuhmillerL.M.van WijkG.M.T.van den BoschH.GardnerM.F.AldernK.A., and RichmanD.D. (1993) Acyclovir diphosphate dimyristoylglycerol: A phospholipid prodrug with activity against acyclovir-resistant herpes simplex virus. Proc Natl Acad Sci USA90: 11835–11839.
14.
JohnsonM.A.AhluwaliaG.ConnellyM.C.CooneyD.A.BroderS.JohnsD.G., and FridlandA. (1988) Metabolic pathway for the activation of the antiretroviral agent 2′,3′-dideoxyadenosine in human lymphoid cells. J Biol Chem263: 15354–15357.
15.
McGuiganC.PathiranaR.N.BalzariniJ., and De ClercqE. (1993) Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT. J Med Chem36: 1048–1052.
16.
McGuiganC.PathiranaR.N.DaviesM.P.H.BalzariniJ., and De ClercqE. (1994) Diaryl phosphate derivatives act as pro-drugs of AZT with reduced cytotoxicity compared to the parent nucleoside. Bioorg Med Chem Lett4: 427–430.
17.
MeierC.NeumannJ.-M.AndréF.HenninY., and Huynh-DinhT. (1992) O-Alkyl-5′,5′-dinucleoside phosphates as prodrugs of 3′-azidothymidine and cordycepin. J Org Chem57: 7300–7308.
18.
MeyerK.L.MarascoC.J.JrMorris-NatschkeS.L.IshaqK.S.PiantadosiC., and KuceraL.S. (1991) In vitro evaluation of phosphocholine and quaternary ammonium containing lipids as novel anti-HIV agents. J Med Chem34: 1377–1383.
19.
MitsuyaH., and BroderS. (1986) Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus, type lll/lymphadenopathy-associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides. Proc Natl Acad Sci USA83: 1911–1915.
20.
MitsuyaH.WeinholdK.J.FurmanP.A.St. ClairM.H.Nusinoff-LehrmanS.GalloR.C.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 lll/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA82: 7096–7100.
21.
MullahK.B.RaoT.S.BalzariniJ.De ClercqE., and BentudeW.G. (1992) Potential prodrug derivatives of 2′,3′-didehydro-2′,3′-dideoxynucleosides. Preparations and antiviral activities. J Med Chem35: 2728–2735.
22.
PiantadosiC.MarascoC.J.JrMorris-NatschkeS.L.MeyerK.L.GumusF.SurlesJ.R.IshaqK.KuceraL.S.IyerN.WallenC.A.PiantadosiS., and ModestE. (1991) Synthesis and evaluation of novel lipid nucleoside conjugates for anti-HIV-1 activity. J Med Chem34: 1408–1414.
23.
PidgeonC.MarkovichR.J.LiuM.D.HolzerT.J.NovakR.M., and KeyerK.A. (1993) Antiviral Phospholipids. Anti-HIV drugs conjugated to the glycerol backbone of phospholipids. J Biol Chem268: 7773–7778.
24.
PopovicM.SarngadharanM.C.ReadE., and GalloR.C. (1984) Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AlDS. Science224: 497–500.
25.
PuechF.GosselinG.LefebvreI.PomponA.AubertinA.M.KirnA., and ImbachJ.L. (1993) Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process. Antiviral Res22: 155–174.
26.
QuiX., and PidgeonC. (1994) Membrane properties of antiviral phospholipids containing heteroatoms in the acyl chains. Biochemistry33: 960–972.
27.
SergheraertC.PierlotC.TartarA.HeninY., and LemaitreM. (1993) Synthesis and anti-HIV evaluation of D4T and D4T 5′-monophosphate prodrugs. J Med Chem36: 826–830.
28.
StarnesM.C., and ChengY.-C. (1987) Cellular metabolism of 2′-3′ dideoxy-cytidine, a compound active against human immunodeficiency virus in vitro. J Biol Chem262: 988–991.
29.
ThomsonW.NichollsD.IrwinW.J.Al-MushadaniJ.FreemanS.KarpasA.PetrikJ.MahmoodN., and HayA.J. (1993) Synthesis, bioactivation and anti-HIV activity of the Bis(4-acyloxybenzyl) and mono(4-acyloxybenzyl) esters of the 5′-monophosphate of AZT. J Chem Soc Perkin Trans1: 1239–1245.
30.
van WijkG.M.T.HostetlerK.Y., and van den BoschH. (1991) Lipid conjugates of antiretroviral agents: release of antiretroviral nucleoside monophosphates by a nucleoside diphosphate diglyceride hydrolase activity from rat liver mitochondria. Biochim Biophys Acta1084: 307–310.
31.
van WijkG.M.T.HostetlerK.Y.KronemanE.RichmanD.D.SridharC.N.KumarR., and van der BoschH. (1994) Synthesis and antiviral activity of 3′-azido-3′-deoxythymidine triphosphate distearoylglycerol: a novel phospholipid conjugate of the anti-HIV agent AZT. Chem Phys Lipids70: 213–222.
32.
WelchC.J.LarsoonA.EricsonA.C.ObergB.DatemaR., and ChattopadhyayaJ. (1985) The chemical synthesis and antiviral properties of an acyclovir-phospholipid conjugate. Acta Chem ScandB 39: 47–54.
