9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP): A novel agent with anti-human immunodeficiency virus activity in vitro and potent anti-moloney murine sarcoma virus activity in vivo

  • L. Naesens
  • J. Balzarini
  • I. Rosenberg
  • A. Holý
  • E. De Clercq
New Antimicrobial Agents


9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) is a potent inhibitor of the replication of human immunodeficiency virus (HIV) in human T-lymphocyte MT-4 cells (50% effective dose: 2 µM). PMEDAP strongly inhibited Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H/3T3 embryo fibroblasts and caused a dose-dependent suppression of tumor formation and mortality in newborn mice inoculated with MSV. Even at a dose as low as 0.25 mg/kg/day, PMEDAP effected a significant delay in tumor appearance and an enhancement of the survival rate of tumor-bearing mice. PMEDAP proved fivefold more efficacious as an anti-MSV agent than 9-(2-phosphonylmethoxyethyl)-adenine (PMEA), which has been previously shown to exhibit strong antiretroviral efficacy in vivo. However, PMEDAP was also more toxic, so that its therapeutic index was equivalent to that of PMEA.


Human Immunodeficiency Virus Adenine Effective Dose Tumor Formation Therapeutic Index 
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  1. 1.
    Barré-Sinoussi, F., Chermann, J. C., Rey, R., Nugeyre, M. T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vézinet-Brun, F., Rouzioux, C., Rozenbaum, W., Montagnier, L. Isolation of a T cell lymphocytic virus from a patient at risk for acquired immunodeficiency syndrome (AIDS). Science 1983, 220: 868–871.PubMedGoogle Scholar
  2. 2.
    Gallo, R. C., Salahuddin, S. Z., Popovic, M., Sherer, G., Kaplan, M., Haynes, B. F., Parker, T. J., Redfield, R., Oleske, J., Safai, B., White, G., Foster, P., Markham, P. D. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984, 224: 500–503.PubMedGoogle Scholar
  3. 3.
    Daniel, M. D., Letvin, N. L., Sehgal, P. K., Hunsmann, G., Schmidt, D. K., King, N. W., Desrosiers, R. C. Long-term persistent infection of macaque monkeys with the simian immunodeficiency virus. Journal of General Virology 1987, 68: 3183–3189.PubMedGoogle Scholar
  4. 4.
    Pedersen, N. C., Ho, E. W., Brown, M. L., Yamamoto, J. K. Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome. Science 1987, 235: 790–793.PubMedGoogle Scholar
  5. 5.
    Filice, G., Cereda, P. M., Varnier, O. E. Infection of rabbits with human immunodeficiency virus. Nature 1988, 335: 366–369.PubMedGoogle Scholar
  6. 6.
    Ruprecht, R. M., O'Brien, L. G., Rossoni, L. D., Nusinoff-Lehrman, S. Suppression of mouse viraemia and retroviral disease by 3′-azido-3′-deoxythymidine. Nature 1986, 323: 467–469.CrossRefPubMedGoogle Scholar
  7. 7.
    Balzarini, J., Pauwels, R., Baba, M., Herdewijn, P., De Clercq, E., Broder, S., Johns, D. G. The in vitro and in vivo anti-retrovirus activity and intracellular metabolism of 3′-azido-2′,3′-dideoxythymidine and 2′,3′-dideoxycytidine are highly dependent on the cell species. Biochemical Pharmacology 1988, 37: 897–903.CrossRefPubMedGoogle Scholar
  8. 8.
    Balzarini, J., Naesens, L., Herdewijn, P., Rosenberg, I., Holý, A., Pauwels, R., Baba, M., Johns, D. G., De Clercq, E. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proceedings of the National Academy of Sciences of the USA 1989, 86: 332–336.PubMedGoogle Scholar
  9. 9.
    Mosier, D. E., Yetter, R. A., Morse, H. C. Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice. Journal of Experimental Medicine 1985, 161: 766–784.CrossRefPubMedGoogle Scholar
  10. 10.
    Pauwels, R., Balzarini, J., Schols, D., Baba, M., Desmyter, J., Rosenberg, I., Holý, A., De Clercq, E. Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrobial Agents and Chemotherapy 1988, 32: 1025–1030.PubMedGoogle Scholar
  11. 11.
    Holý, A., Rosenberg, I. Synthesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds. Collection of Czechoslovak Chemical Communications 1987, 52: 2801–2809.Google Scholar
  12. 12.
    Harada, S., Koyanagi, Y., Yamamoto, N. Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay. Science 1985, 229: 563–566.PubMedGoogle Scholar
  13. 13.
    Pauwels, R., De Clercq, E., Desmyter, J., Balzarini, J., Goubau, P., Herdewijn, P., Vanderhaeghe, H., Vandeputte, M. Sensitive and rapid assay on MT-4 cells for detection of antiviral compounds against the AIDS virus. Journal of Virological Methods 1987, 16: 171–185.CrossRefPubMedGoogle Scholar
  14. 14.
    Balzarini, J., Pauwels, R., Baba, M., Robins, M. J., Zou, R., Herdewijn, P., De Clercq, E. The 2′,3′-dideoxyriboside of 2,6-diaminopurine selectively inhibits human immunodeficiency virus (HIV) replication in vitro. Biochemical and Biophysical Research Communications 1987, 145: 269–276.CrossRefPubMedGoogle Scholar
  15. 15.
    Popovic, M., Sarngadharan, M. G., Read, E., Gallo, R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 1984, 224: 497–500.PubMedGoogle Scholar
  16. 16.
    De Clercq, E., Merigan, T. C. Moloney sarcoma virus-induced tumors in mice: inhibition or stimulation by (poly rI):(poly rC). Proceedings of the Society for Experimental Biology and Medicine 1971, 137: 590–594.Google Scholar

Copyright information

© Friedr. Viewey & Sohn Verlagsgesellschaft mbH 1989

Authors and Affiliations

  • L. Naesens
    • 1
  • J. Balzarini
    • 1
  • I. Rosenberg
    • 2
  • A. Holý
    • 2
  • E. De Clercq
    • 1
  1. 1.Rega Institute for Medical ResearchKatholieke Universiteit LeuvenLeuvenBelgium
  2. 2.Institute of Organic Chemistry and BiochemistryCzechoslovak Academy of SciencesPrague 6Czechoslovakia

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