The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: A structure-activity relationship

Journal of Medicinal Chemistry

Volumn 42, Issue 3, 1999, Pages 393-399

  Siddiqui, Adam Q ^a   Ballatore, Carlo ^a   McGuigan, Christopher ^a   De Clercq, Erik ^b   Balzarini, Jan ^b  

^a CARDIFF UNIVERSITY   (United Kingdom)

^b REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

2',3' DIDEHYDRO 2',3' DIDEOXYTHYMIDINE 5' [4 CHLOROPHENYL(METHOXYALANINYL)PHOSPHATE]; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ARYLPHOSPHORAMIDATE DERIVATIVE; ESTERASE; LIVER ENZYME; OCTANOL; PRODRUG; STAVUDINE; THYMIDINE KINASE; UNCLASSIFIED DRUG; WATER;

ANIMAL CELL; ANIMAL TISSUE; ANTIVIRAL ACTIVITY; ARTICLE; CELL CULTURE; CELL STRAIN 3T3; CONTROLLED STUDY; DRUG POTENCY; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS; LIPOPHILICITY; MOUSE; NONHUMAN; PARTITION COEFFICIENT; STRUCTURE ACTIVITY RELATION; SWINE;

3T3 CELLS; ANIMALS; ANTI-HIV AGENTS; CELL LINE; CELLS, CULTURED; ESTERASES; HIV-1; HIV-2; HUMANS; LIVER; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MICROBIAL SENSITIVITY TESTS; ORGANOPHOSPHORUS COMPOUNDS; SPECTROMETRY, MASS, FAST ATOM BOMBARDMENT; STAVUDINE; STRUCTURE-ACTIVITY RELATIONSHIP; SWINE; THIONUCLEOTIDES;

EID: 0033048195     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9803931     Document Type: Article

References (33)

1. De Clercq, E. In search of a Selective Antiviral Chemotherapy. Clin. Microbiol. Rev. 1997, 10, 674-693.
2. Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St. Clair, M. H.; Nusinoff-Lehrman, S.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.; Broder, S. 3′-Azido-3′-deoxythymidine (BWA509U): An agent that inhibits the infectivity and cytopathic effect of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 7096-7100.
3. Mitsuya, H.; Broder, S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus, type III/ lymphadenopathy-associated virus (HTLV III/LAV) by 2′,3′-didoxynucleosides. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1911-1915.
4. Balzarini, J.; Kang, G.-J.; Dalal, M.; Herdewijn, P.; De Clercq, E.; Broder, S.; Johns, D. G. The anti-HTLV-III (anti-HIV) and cytotoxic activity of 2′,3′-didehydro-2′,3′-dideoxyribonucleosides. A comparison with their parental 2′,3′-dideoxyribonucleosides. Mol. Pharmacol. 1987, 32, 162-167.
5. Herdewijn, P.; Balzarini, J.; De Clercq, E.; Pauwels, R.; Baba, M.; Broder, S.; Vanderhaeghe, H. 3′-Substituted 2′,3′-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J. Med. Chem. 1987, 30, 1270-1278.
6. Balzarini, J.; Baba, M.; Pauwels, R.; Herdewijn, P.; De Clercq, E. Anti-retrovirus activity of 3′-fluoro-and 3′-azido-substituted pyrimidine 2′,3′-dideoxynucleoside analogues. Biochem. Pharmacol. 1988, 37, 2847-2856.
7. Balzarini, J.; Cooney, D. A.; Dalal, M.; Kang, G.-J.; Cupp, J. E.; De Clercq, E.; Broder, S.; Johns, D. G. 2′,3′-Dideoxycytidine: regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis. Mol. Pharmacol. 1987, 32, 798-806.
8. Starnes, M. G.; Cheng, Y.-C. Cellular metabolism of 2′,3′-Dideoxycytidine, a compound active against human immunodeficiency virus in vitro. J. Biol. Chem. 1987, 32, 798-806.
9. Hao, Z.; Cooney, D. A.; Farquhar, D.; Perno, C. F.; Zhang, K.; Masood, R.; Wilson, Y.; Hartman, N. R.; Balzarini, J.; Johns, D. G. Potent chain termination activity and selective inhibition of human immunodeficiency virus reverse transcriptase by 2′,3′-Dideoxyuridine-5′-triphosphate. Mol. Pharmacol. 1990, 37, 157-163.
10. Johnson, M. A; Ahluwalia, G.; Connelly, M. C.; Cooney, D. A.; Broder, S.; Johns, D. G.; Fridland, A. Metabolic pathways for the activation of the antiretroviral agent 2′,3′-dideoxyadenosine in human lymphoid cells. J. Biol. Chem. 1988, 263, 15354-15357.
11. Johnson, M. A.; Fridland, A. Phosphorylation of 2′,3′-dideoxy-inosine by cytosolic 5′-nucleotidase of human lymphoid cells. Mol. Pharmacol. 1989, 36, 291-295.
12. Perno, C. F.; Yarchoan, R.; Cooney, D. A.; Hartman, N. R.; Webb, D. S. A; Hao, Z.; Mitsuya, H.; Johns, D. G.; Broder, S. Replication of human immuodeficiency virus in monocytes. J. Exp. Med. 1989, 169, 933-951.
13. Jones, R. J.; Bischofberger, W. Minireview - Nucleotide Prodrugs. Antiviral Res. 1995, 27, 1-17.
14. Meier, C. Pro-Nucleotides Recent Advances in the Design of Efficient Tools for the Delivery of Biologically Active Nucleosides Monophosphates. Synlett 1998, 233.
15. Balzarini, J.; Kruining, J.; Wedgwood, O.; Pannecouque, C.; Aquaro, S.; Perno, C. F.; Naesens, L.; Witvrouw, M.; Heijtink, R.; De Clercq, E.; McGuigan, C. Conversion of 2′,3′-dideoxyadenosine (ddA) and 2′,3′-didehydro-2′,3′-dideoxyadenosine (d4A) to their corresponding aryloxyphosphoramidate derivatives markedly potentiates their activity against human immunodeficiency virus and hepatitis B virus. FEBS Lett. 1997, 410, 324-328.
16. McGuigan, C.; Cahard, D.; Sheeka, H. M.; De Clercq, E.; Balzarini, J. Phosphoramidate derivatives of d4T with improved anti-HIV efficacy retain full activity in thymidine kinase-deficient cells. Bioorg. Med. Chem. Lett. 1996, 6, 1183-1186.
17. McGuigan, C.; Cahard, D.; Sheeka, H. M.; De Clercq, E.; Balzarini, J. Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. J. Med. Chem. 1996, 39, 1748-1753.
18. Baba, M.; Pauwels, R.; Herdewifn, P.; De Clercq, E.; Desmyter, J.; Vandeputte, M. Both 2′,3′-dideoxythmidine and its 2′,3′-unsaturated derivative (2′,3′-dideoxythymidine) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem. Biophys. Res. Commun. 1987, 142, 128-134.
19. Mansuri, M. M.; Hitchcock, M. J. M.; Buroker, R. A.; Bregman, C. L.; Ghazzouli, I.; Desiderio, J. V.; Starrett, J. E., Jr.; Sterzycki, R. Z.; Martin, J. C. Comparison of in vitro biological properties and mouse toxicities of three thymidine analogues active against human immunodeficiency virus. Antimicrob. Agents Chemother. 1990, 34, 637-641.
20. (a) Furman, P. A.; Fyfe, J. A.; St. Clair, M. H.; Weinhold, K.; Rideout, J. L.; Freeman, J. A.; Lehrman, S. N.; Bolognesi, D. P.; Broder, S.; Mitsuya, H.; Barry, D. W. Phosphorylation of 3′-Azido-3′-dideoxythymidine and Selective Interaction of the 5′-Triphosphate with Human Immunodeficiency Virus Reverse-Transcriptase. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 8333-8337.
21. (b) Balzarini, J.; Herdewijn, P.; De Clercq, E. 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. Chem. 1989, 264, 6127-6133.
22. Valette, G.; Pompon, A.; Girardet, J. L.; Cappellacci, L.; Franchetti, P.; Grifantini, M.; LaColla, P.; Loi, A. G.; Perigaud, C.; Gosselin, G.; Imbach, J. L. Decomposition pathways and in vitro HIV inhibitory effects of isoddA pronucleotides - toward a rational approach for intracellular delivery of nucleoside 5′-monophosphates. J. Med. Chem. 1996, 39, 1981-1990.
23. Balzarini, J.; Egberink, H.; Hartmann, K.; Cahard, D.; Vahlenkamp, T.; Thormar, H.; De Clercq, E.; McGuigan, C. Antiretrovirus specificity and intracellular metabolism of 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine) and its 5′-monophosphate triester prodrug So324. Mol. Pharmacol. 1996, 50, 1207-1213.
24. McGuigan, C.; Tsang, H.-W.; Cahard, D.; Turner, S.; Velazquez, S.; Salgado, A.; Bidois, L.; Naesens, L.; De Clercq, E.; Balzarini, J. Phosphoramidate derivatives of d4T as inhibitors of HIV: The effect of amino acid variation. Antiviral Res. 1997, 35, 195-204.
25. Horwitz, J. P.; Chua, J.; DaRooge, M. A.; Noel, M.; Klindt, I. L. Nucleosides. IX. The formation of 2′,3′-unstaurated pyrimidine nucleosides via a novel β-elimination reaction. J. Org. Chem. 1996, 31, 205-211.
26. Mansuri, M. M.; Starrett, J. E., Jr.; Ghazzouli, I.; Hitchcock, M. J. M.; Sterzycki, R. Z.; Brankovan, V.; Lin, T. S.; August, E. M.; Prussoff, W. H.; Sommadossi, J. P.; Martin, J. C. 1-(2′,3′-dideoxy-β-D-glycero-pent-2-enfuranosyl)thymine. A highly Potent and Selective Anti-HIV Agent. J. Med. Chem. 1989, 32, 462-446.
27. McGuigan, C.; Pathirana, R. N.; Balzarini, J.; De Clercq, E. Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT. J. Med. Chem. 1993, 36, 1048-1052.
28. McGuigan, C.; Davies, M.; Pathirana, R.; Mahmood, N.; Hay, A. J. Synthesis and anti-HIV activity of some novel diaryl phosphate derivatives of AZT. J. Med. Chem. 1996, 39, 1748-1753.
29. Hansch, C.; Leo, A. Substitution Constants for Correlation Analysis in Chemistry and Biology; Wiley-Interscience: New York, 1979.
30. Balzarini, J.; Cools, M.; De Clercq, E. Estimation of the Lipophilicity of Anti-HIV Nucleoside Analogues by Determination of the Partition-Coefficient and Retention Time on a Lichrospher-60 RP-8 HPLC Column. Biochem. Biophys. Res. Commun. 1989, 158, 413-422.
31. Junge, W.; Heymann, E. Characterisation of the isoenzymes of pig-liver esterase. Eur. J. Biochem. 1979, 95, 519-525.
32. Junge, W.; Heymann, E.; Krisch, K.; Hollandt, H. Human Liver Carboxyesterase. J. Biochem. Biophys. 1974, 165, 749-763 and references therein.
33. Balzarini, J.; Karlsson, A.; Aquaro, S.; Perno, C.-F.; Cahard, D.; Naesens, L.; De Clercq, E. Mechanism of Anti-Hiv Action of Masked Alaninyl d4T-MP Derivatives. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 7295-7299