The potency and selectivity index of the AZT-phenyl phosphate derivatives in thymidine kinase (TK)-deficient T cells were substantially enhanced by introducing a single para-bromo substituent in the phenyl moiety. AZT-5′-(p-bromophenyl methoxyalaninyl phosphate) was 43-fold more potent than AZT-5′-(phenyl methoxyalaninyl phosphate) and was fivefold more potent than AZT in inhibiting human immunodeficiency virus (HIV) replication in TK-deficient CEM cells.
BalzariniJHerdewijnP 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. Journal of Biological Chemistry264: 6127–6133.
2.
ChuCK & SchinaziR F (1989) 2′,3′-dideoxy-5-substituted uridines and related compounds as antiviral agents. U.S. Patent 4,841,039.
3.
EriceALielerCLMeyersDESannerundK JIrvinJDBalfourHH & UckunFM (1993) Inhibition of zidovudine (AZT)-sensitive strains of human immuno deficiency virus type 1 by pokeweed antiviral protein targeted to CD4+ cells. Antimicrobial Agents and Chemotherapy37: 835–838.
4.
FurmanPAFyfeJASt. ClairMHWeinholdKRideoutJLFreemanGALehrmanNusinoff SBolognesiDPBorderSMitsuyaH & BarryDW (1986) Phosphorylation of 3′-azido-3′deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proceedings of the National Acadamy of Sciences, USA83: 8333.
5.
HaoZCooneyDAHartmanNRPernoCFFridlandADe VicoALSarngadharanMGBorderS & JohnsDG (1988) Factors determining the activity of 2′-3′-dideoxynucleosides in suppressing human immunodeficiency virus in vitro. Molecular Pharmacology34: 431.
6.
McGuiganCPathiranaRNMahmoodNDevineKG & HayAJ (1992) Aryl phosphate derivatives of AZT retain activity against HIV-1 in cell lines which are resistant to the action of AZT. Antiviral Research17: 311.
7.
McGuiganCPathiranaRNBalzariniJ & De ClercqE (1993) Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT. Journal of Medicinal Chemistry36: 1048–1052.
8.
McGuiganCCahardDSheekaHMDe ClercqE & BalzariniJ (1996a) Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. Journal of Medicinal Chemistry39: 1748–1753.
9.
McGuiganCCahardDSheekaHMDe ClercqE & BalzariniJ (1996b) Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in the thymidine kinase-deficient cells. Bioorganic Medicinal Chemistry Letters6: 1183.
10.
McInteeEJRemmelR PSchinaziRFAbrahamTW & WagnerCR (1997) Probing the mechanism of action and decomposition of amino acid phosphomonoester amidates of antiviral nucleoside prodrugs. Journal of Medicinal Chemistry40: 3323–3331.
11.
VigRVenkatachalamTK & UckunFM (1998a) d4T-5′-[p-bromophenyl methoxyalaninyl phosphate] as a potent and non-toxic anti-HIV agent. Antiviral Chemistry & Chemotherapy9: 445–448.
12.
VigRVenkatachalamTKJanS-T & UckunFM (1998b) Aryl phosphate derivatives of 3′-deoxythymidine are not potent anti-HIV agents. Antiviral Chemistry & Chemotherapy9: 439–443.
13.
VenkatachalamTKTaiH-LVigRChenC-LJanS-T & UckunFM (1998) Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4t-phenyl methoxyalaninyl phosphate derivatives. Bioorganic Medicinal Chemistry Letters8: 3121–3126.
14.
UckunFMChelstromLMTuel-AhlgrenLDibirdikIIrvinJDLanglieMC & MyersDE (1998) TXU (Anti-CD7)-pokeweed antiviral protein as a potent inhibitor of human immunodeficiency virus. Antimicrobial Agents and Chemotherapy42: 383–388.
15.
ZarlingJMMoranPAHaffarOSiasJRichmanDDSpinaCAMyersDEKuebelbeckVLedbetterJA & UckunFM (1990) Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies. Nature, 347: 92–95.