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. 1989 Dec;33(12):2083–2088. doi: 10.1128/aac.33.12.2083

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1.

R Koshida 1, S Cox 1, J Harmenberg 1, G Gilljam 1, B Wahren 1
PMCID: PMC172825  PMID: 2533474

Abstract

One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Balzarini J., Baba M., Pauwels R., Herdewijn P., De Clerq E. Anti-retrovirus activity of 3'-fluoro- and 3'-azido-substituted pyrimidine 2',3'-dideoxynucleoside analogues. Biochem Pharmacol. 1988 Jul 15;37(14):2847–2856. doi: 10.1016/0006-2952(88)90049-4. [DOI] [PubMed] [Google Scholar]
  2. Balzarini J., Baba M., Pauwels R., Herdewijn P., Wood S. G., Robins M. J., de Clercq E. Potent and selective activity of 3'-azido-2,6-diaminopurine-2',3'-dideoxyriboside, 3'-fluoro-2,6-diaminopurine-2',3'-dideoxyriboside, and 3'-fluoro-2',3'-dideoxyguanosine against human immunodeficiency virus. Mol Pharmacol. 1988 Mar;33(3):243–249. [PubMed] [Google Scholar]
  3. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  4. Bazin H., Chattopadhyaya J., Datema R., Ericson A. C., Gilljam G., Johansson N. G., Hansen J., Koshida R., Moelling K., Oberg B. An analysis of the inhibition of replication of HIV and MuLV by some 3'-blocked pyrimidine analogs. Biochem Pharmacol. 1989 Jan 1;38(1):109–119. doi: 10.1016/0006-2952(89)90157-3. [DOI] [PubMed] [Google Scholar]
  5. Cheng Y. C., Dutschman G. E., Bastow K. F., Sarngadharan M. G., Ting R. Y. Human immunodeficiency virus reverse transcriptase. General properties and its interactions with nucleoside triphosphate analogs. J Biol Chem. 1987 Feb 15;262(5):2187–2189. [PubMed] [Google Scholar]
  6. Chou T. C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. doi: 10.1016/0065-2571(84)90007-4. [DOI] [PubMed] [Google Scholar]
  7. De Clercq E. Chemotherapeutic approaches to the treatment of the acquired immune deficiency syndrome (AIDS). J Med Chem. 1986 Sep;29(9):1561–1569. doi: 10.1021/jm00159a001. [DOI] [PubMed] [Google Scholar]
  8. Furman P. A., Fyfe J. A., St Clair M. H., Weinhold K., Rideout J. L., Freeman G. A., Lehrman S. N., Bolognesi D. P., Broder S., Mitsuya H. Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8333–8337. doi: 10.1073/pnas.83.21.8333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  10. Haertle T., Carrera C. J., Wasson D. B., Sowers L. C., Richman D. D., Carson D. A. Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives. J Biol Chem. 1988 Apr 25;263(12):5870–5875. [PubMed] [Google Scholar]
  11. Hartmann H., Vogt M. W., Durno A. G., Hirsch M. S., Hunsmann G., Eckstein F. Enhanced in vitro inhibition of HIV-1 replication by 3'-fluoro-3'-deoxythymidine compared to several other nucleoside analogs. AIDS Res Hum Retroviruses. 1988 Dec;4(6):457–466. doi: 10.1089/aid.1988.4.457. [DOI] [PubMed] [Google Scholar]
  12. Hartshorn K. L., Vogt M. W., Chou T. C., Blumberg R. S., Byington R., Schooley R. T., Hirsch M. S. Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Agents Chemother. 1987 Feb;31(2):168–172. doi: 10.1128/aac.31.2.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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 Aug;30(8):1270–1278. doi: 10.1021/jm00391a003. [DOI] [PubMed] [Google Scholar]
  14. Kim C. H., Marquez V. E., Broder S., Mitsuya H., Driscoll J. S. Potential anti-AIDS drugs. 2',3'-Dideoxycytidine analogues. J Med Chem. 1987 May;30(5):862–866. doi: 10.1021/jm00388a020. [DOI] [PubMed] [Google Scholar]
  15. Koshida R., Vrang L., Gilljam G., Harmenberg J., Oberg B., Wahren B. Inhibition of human immunodeficiency virus in vitro by combinations of 3'-azido-3'-deoxythymidine and foscarnet. Antimicrob Agents Chemother. 1989 May;33(5):778–780. doi: 10.1128/aac.33.5.778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  17. Mar E. C., Patel P. C., Cheng Y. C., Fox J. J., Watanabe K. A., Huang E. S. Effects of certain nucleoside analogues on human cytomegalovirus replication in vitro. J Gen Virol. 1984 Jan;65(Pt 1):47–53. doi: 10.1099/0022-1317-65-1-47. [DOI] [PubMed] [Google Scholar]
  18. Marquez V. E., Tseng C. K., Kelley J. A., Mitsuya H., Broder S., Roth J. S., Driscoll J. S. 2',3'-Dideoxy-2'-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem Pharmacol. 1987 Sep 1;36(17):2719–2722. doi: 10.1016/0006-2952(87)90254-1. [DOI] [PubMed] [Google Scholar]
  19. Mitsuya H., Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1911–1915. doi: 10.1073/pnas.83.6.1911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mitsuya H., Broder S. Strategies for antiviral therapy in AIDS. 1987 Feb 26-Mar 4Nature. 325(6107):773–778. doi: 10.1038/325773a0. [DOI] [PubMed] [Google Scholar]
  21. Mitsuya H., Jarrett R. F., Matsukura M., Di Marzo Veronese F., DeVico A. L., Sarngadharan M. G., Johns D. G., Reitz M. S., Broder S. Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2',3'-dideoxynucleosides in vitro. Proc Natl Acad Sci U S A. 1987 Apr;84(7):2033–2037. doi: 10.1073/pnas.84.7.2033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mitsuya H., Weinhold K. J., Furman P. A., St Clair M. H., Lehrman S. N., Gallo R. C., Bolognesi D., Barry D. W., Broder S. 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 U S A. 1985 Oct;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Oberg B. Antiviral therapy. J Acquir Immune Defic Syndr. 1988;1(3):257–266. [PubMed] [Google Scholar]
  24. Pauwels R., Baba M., Balzarini J., Herdewijn P., Desmyter J., Robins M. J., Zou R. M., Madej D., De Clercq E. Investigations on the anti-HIV activity of 2',3'-dideoxyadenosine analogues with modifications in either the pentose or purine moiety. Potent and selective anti-HIV activity of 2,6-diaminopurine 2',3'-dideoxyriboside. Biochem Pharmacol. 1988 Apr 1;37(7):1317–1325. doi: 10.1016/0006-2952(88)90789-7. [DOI] [PubMed] [Google Scholar]
  25. Richman D. D., Fischl M. A., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Hirsch M. S. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. doi: 10.1056/NEJM198707233170402. [DOI] [PubMed] [Google Scholar]
  26. Sandstrom E. G., Kaplan J. C., Byington R. E., Hirsch M. S. Inhibition of human T-cell lymphotropic virus type III in vitro by phosphonoformate. Lancet. 1985 Jun 29;1(8444):1480–1482. doi: 10.1016/s0140-6736(85)92255-x. [DOI] [PubMed] [Google Scholar]
  27. Sarin P. S., Taguchi Y., Sun D., Thornton A., Gallo R. C., Oberg B. Inhibition of HTLV-III/LAV replication by foscarnet. Biochem Pharmacol. 1985 Nov 15;34(22):4075–4079. doi: 10.1016/0006-2952(85)90392-2. [DOI] [PubMed] [Google Scholar]
  28. Stanwick T. L., Schinazi R. F., Campbell D. E., Nahmias A. J. Combined antiviral effect of interferon and acyclovir on herpes simplex virus types 1 and 2. Antimicrob Agents Chemother. 1981 Apr;19(4):672–674. doi: 10.1128/aac.19.4.672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vogt M. W., Hartshorn K. L., Furman P. A., Chou T. C., Fyfe J. A., Coleman L. A., Crumpacker C., Schooley R. T., Hirsch M. S. Ribavirin antagonizes the effect of azidothymidine on HIV replication. Science. 1987 Mar 13;235(4794):1376–1379. doi: 10.1126/science.2435003. [DOI] [PubMed] [Google Scholar]
  30. Vogt M., Hirsch M. S. Prospects for the prevention and therapy of infections with the human immunodeficiency virus. Rev Infect Dis. 1986 Nov-Dec;8(6):991–1000. doi: 10.1093/clinids/8.6.991. [DOI] [PubMed] [Google Scholar]
  31. Yarchoan R., Perno C. F., Thomas R. V., Klecker R. W., Allain J. P., Wills R. J., McAtee N., Fischl M. A., Dubinsky R., McNeely M. C. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet. 1988 Jan 16;1(8577):76–81. doi: 10.1016/s0140-6736(88)90283-8. [DOI] [PubMed] [Google Scholar]

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