Skip to main content
SpringerLink
Log in

Structure-activity relationships and conformational features of antiherpetic pyrimidine and purine nucleoside analogues. A review

  • Published:
Pharmacy World and Science Aims and scope Submit manuscript

Abstract

A rational approach to the design of antiherpetic nucleoside analogues is based in part on the broad specificity ol virus- coded thymidine kinases. Herpes virus thymidine kinase ‘activates’ many 5-substituted 2′-deoxyuridines, analogues ol thymidinc (e.g., idoxuridine, trifluridine, edoxudine, brivudine), 5-substituted arabinofuranosyluracil derivatives (e.g., 5-Et-Ara-U, BV-Ara-U, Cl-Ara-U), acyclonucleosides of guanine (e.g., aciclovir, ganciclovir, penciclovir), and purine nucleosides with the penlafuranosyl ring replaced by a cyclobutane ring (e.g., cyclobut-G, cyclobut-A). Activation involves selective, and frequently regiospecific, phosphorylation ol these analogues to the 5′-monophosphales. These are further phosphorylated by cellular enzymes to the 5′-triphosphates, which are usually competitive inhibitors of the viral-coded DNA polymerases. Some analogues are also incorporated into viral, and to a lesser extent cellular, DNA. A recent, unusual, exception is human cytomegalovirus, which does not code for a thymidine kinase, but for a protein with the sequence characteristics of protein kinase and which phosphorylates ganciclovir to its 5′-monophosphate. The interaction of the analogues with cellular catabolic enzymes such as uridine and thymidine nucleoside phosphorylases is also discussed, as is the relationship between physicochemical properties (configuration, conformation, electronic and hydrophobic parameters) and antiviral activities, with particular reference to those drugs that are licensed, or under consideration, for clinical use.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chalberg MD, Kelly TJ. Animal virus DNA replication. Annu Rev Biochem 1989;58:671–717.

    PubMed  Google Scholar 

  2. Shannon WM, Schabel FM Jr. Antiviral agents as adjuncts in cancer chemotherapy. Pharmacol Ther 1980;11:263–390.

    PubMed  Google Scholar 

  3. Grunert ER. Search for antiviral agents. Annu Rev Microbiol 1979;33:335–53.

    PubMed  Google Scholar 

  4. Nahmias AJ, Roizman B. Infection with herpes simplex viruses 1 and 2. N Engl J Med 1973;289:667–74.

    PubMed  Google Scholar 

  5. Stevens JG. Human herpes viruses: a consideration of the latent state. Microbiol Rev 1989;53:318–22.

    PubMed  Google Scholar 

  6. Robinson JE, Smith D, Niederman J. Plasmacytic differentiation of circulating Epstein-Barr virus-infected B lymphocytes during acute infectious mononucleosis. J Exp Med 1981;153:235–44.

    PubMed  Google Scholar 

  7. Macher AM, Cheryl M, Reichert CM, Straus SE, Longo DL, Parillo J, et al. Death in the AIDS patient: role of cytomegalovirus. N Engl J Med 1983;309:1454.

    Google Scholar 

  8. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986;234:596–603.

    PubMed  Google Scholar 

  9. Lawrence GL, Chee M, Craxton MA, Gompels UA, Honess RW, Barrell BG. Human herpes virus 6 is closely related to human cytomegalovirus. J Virol 1990;64:287–99.

    PubMed  Google Scholar 

  10. Lusso PL, Gallo RC, De Rocco SE, Markham PD. CD4 is not the membrane receptor for HHV-6. Lancet 1989;1:730.

    Google Scholar 

  11. Hoffman PJ, Cheng YC. The deoxyribonuclease induced after infection of KB cells by herpes simplex virus type 1 or type 2. J Biol Chem 1977;253:3557–62.

    Google Scholar 

  12. Littler E, Stuart AD, Chee MS. Human cytomegalovirusUL 97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue. Nature 1992;358:160–2.

    PubMed  Google Scholar 

  13. Shugar D. Phosphorylating enzymes involved in activation of chemotherapeutic nucleosides and nucleotides. In: Shugar D, Rode W, Borowski E, editors. Molecular aspects of chemotherapy. Proceedings of the Third International Symposium on Molecular Aspects of Chemotherapy; 1991 Jun 19–21; Gdańsk. Warszawa: Springer-Verlag-PWN, 1992:239–70.

    Google Scholar 

  14. Gentry GA. Viral thymidine kinases and their relatives. Pharmacol Ther 1992;54:319–55.

    PubMed  Google Scholar 

  15. Chen MS, Prusoff WH. Association of thymidine kinase activity with pyrimidine deoxyribonucleoside kinase induced by herpes simplex virus. J Biol Chem 1978;253:1325–7.

    PubMed  Google Scholar 

  16. Chen MS, Walker I, Prusoff WH. Kinetic studies of herpes simplex virus type 1-encoded thymidine and thymidylate kinase, a multifunctional enzyme. J Biol Chem 1979;254:10747–53.

    PubMed  Google Scholar 

  17. Knopf KW. Properties of herpes simplex virus DNA polymerase and characterization of its associated exonuclease activity. Eur J Biochem 1979;98:231–44.

    PubMed  Google Scholar 

  18. Ostrander M, Cheng YC. Properties of herpes simplex virus type 1 and type 2 DNA polymerase. Biochim Biophys Acta 1980;609:232–45.

    PubMed  Google Scholar 

  19. Derse D, Cheng YC. Herpes simplex virus type 1 DNA polymerase. J Biol Chem 1981;256:8525–30.

    PubMed  Google Scholar 

  20. Prusoff WH. Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim Biophys Acta 1959;32:295–6.

    PubMed  Google Scholar 

  21. Gauri KK, Malorny G. Chemotherapie der Herpes-infection mit neuen 5-Alkyluracildesoxyribosiden. Naunyn-Schmiedeberg's Arch Pharmacol Exp Pathol 1967;257:21–2.

    Google Scholar 

  22. Elion GB, Furman PA, Fyfe JA, De Miranda P, Beauchamp L, Schaeffer HJ. Selectivity of action of an antiherpetic agent 9-(2-hydroxyethoxymethyl)guanine. Proc Natl Acad Sci USA 1977;74:5716–20.

    PubMed  Google Scholar 

  23. De Clercq E, Descamps J, Barr Pj, Jones AS, Serafinowski P, Walker RT, et al. Comparative study of the potency and selectivity of anti-herpes compounds. In: Skoda J, Langen P, editors. Antimetabolites in biochemistry, biology and medicine. Oxford: Pergamon Press, 1979:275–85.

    Google Scholar 

  24. Hermann EC Jr. Plaque inhibition test for detection of specific inhibitors of DNA containing viruses. Proc Soc Exp Biol Med 1967;107:142–5.

    Google Scholar 

  25. De Clercq E, Descamps J, De Somer P, Barr PJ, Jones AS, Walker RT. (E)-5-(2-Bromovinyl)-2′-deoxyuridine: a potent and selective anti-herpes agent. Proc Natl Acad Sci USA 1979;76:2947–51.

    PubMed  Google Scholar 

  26. De Clercq E, Descamps J, Verhelst G, Jones AS, Walker RT. Antiviral activity of 5-(2-halogenovinyl)-2′-deoxyuridines. In: Current chemotherapy and infectious disease. Proceedings of the 11th ICC and 19th ICAAC 1979. Vol 2. Washington: American Society for Microbiology, 1980:1372–4.

    Google Scholar 

  27. Bergstrom DE, Ruth JL, Reddy PA, De Clercq E. Synthesis of (E)-5-(3,3,3-trifluoro-1-propenyl)-2′-deoxyuridine (TFPedUrd), and related analogs: potent and unusually selective antiviral activity of TFPe-dUrd against HSV-1. J Med Chem 1984;27:279–84.

    PubMed  Google Scholar 

  28. Rahim SG, Duggan MJH, Walker RT, Jones AS, Dyer RL, Balzarini J, et al. Synthesis and biological properties of 2′-deoxy-5-vinyluridine and 2′-deoxy-5-vinylcytidine. Nucleic Acids Res 1982;10:5285–95.

    PubMed  Google Scholar 

  29. De Clercq E, Descamps J, Verhelst G, Walker RT, Jones AS, Torrence PF, et al. Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis 1980;141:536–74.

    Google Scholar 

  30. Park JS, Chang CTC, Schmidt CL, Golander Y, De Clercq E, Descamps J, et al. Oxime and dithiolane derivatives of 5-formyl-2′-deoxyuridine and their 5′-phosphates: antiviral effects and thymidylate synthase inhibition. J Med Chem 1980;23:661–5.

    PubMed  Google Scholar 

  31. De Clercq E, Descamps J, Schmidt CL, Mertes MP. Antiviral activity of 5-methylthiomethyl-2′-deoxyuridine and other 5-substituted 2′-deoxyuridines. Biochem Pharmacol 1979;28:3249–54.

    PubMed  Google Scholar 

  32. Babiuk LA, Meldrum B, Gupta VS, Rouse BT. Comparison of the antiviral effects of 5-methoxymethyldeoxyuridine with 5-iododeoxyuridine, cytosine arabinoside, and adenine arabinoside. Antimicrob Agents Chemother 1975;8:643–50.

    PubMed  Google Scholar 

  33. Griengl H, Schwarz W. Synthesis and antiviral activity of 5′-O- and 3-N-substituted derivatives of 5-(2-chloroethyl)-2′-deoxyuridine. Chem Scripta 1986;26:67–71.

    Google Scholar 

  34. Berens K, Shugar D. Ultraviolet absorption spectra and structure of halogenated uracils and their glycosides. Acta Biochim Polon 1963;10:25–48.

    PubMed  Google Scholar 

  35. Camerman N, Trotter J. The crystal and molecular structure of 5-iodo-2′-deoxyuridine. Acta Crystallogr 1965;18:203–11.

    Google Scholar 

  36. Kulikowski T, Stolarski R, Shugar D. Solution conformations of biologically active 5-substituted pyrimidine 2′-deoxy- and arabinonucleosides. Nucleic Acids Res Symp Ser 1984;14:235–6.

    Google Scholar 

  37. Young DW, Tollin P, Wilson HR. The crystal and molecular structure of thymidine. Acta Crystallogr B 1969;25:1423–32.

    Google Scholar 

  38. Lemieux RU. Configuration and conformation of thymidine. Can J Chem 1960;39:116–20.

    Google Scholar 

  39. Fischer PH, Chen MP, Prusoff WH. The incorporation of 5-iodo-5′-amino-2′,5′-dideoxyuridine and 5-iodo-2′-deoxyuridine into herpes simplex virus DNA. Biochim Biophys Acta 1980;606:236–45.

    PubMed  Google Scholar 

  40. Calabresi P, Cardoso SS, Finch SC, Kligerman MM, Von Essen CF, Chu MY, et al. Initial clinical studies with 5-iodo-2′-deoxyuridine. Cancer Res 1961;21:550–9.

    PubMed  Google Scholar 

  41. Otto MJ, Goz B, Prusoff WH. Antiviral activity of iodinated pyrimidine deoxyribonucleosides. In: Becker YC, editor. Antiviral drugs and interferon, the molecular basis of their activity. Boston: Martinus Nijhoff Publishing, 1984;11–38.

    Google Scholar 

  42. Otto MJ, Lee JJ, Prusoff WH. Effects of nucleoside analogs on the expression of herpes simplex type 1-induced proteins. Antiviral Res 1982;2:267–81.

    PubMed  Google Scholar 

  43. Pontis HG, Degerstedt G, Reichard P. Uridine and deoxyuridine phosphorylases from Ehrlich ascites tumor. Biochim Biophys Acta 1961;51:138–47.

    PubMed  Google Scholar 

  44. Huberman E, Heidelberger C. Mutagenicity to mammalian cells of pyrimidine nudeoside analogs. Mutat Res 1972;14:130–2.

    PubMed  Google Scholar 

  45. Itoi M, Gefter JW, Kaneko N, Ishii Y, Ramer RM, Gasset MA. Teratogenicities of ophthalmic drugs. I. Antiviral ophthalmic drugs. Arch Opthalmol 1975;93:46–51.

    Google Scholar 

  46. Kaufman HE. Clinical cure of herpes simplex keratitis by 5-iodo-2′-deoxyuridine. Proc Soc Exp Biol Med 1962;109:251–2.

    PubMed  Google Scholar 

  47. Heidelberger C, Parsons D, Remy DC. Syntheses of 5-trifluoromethyluracil and 5-trifluoromethyl-2′-deoxyuridine. J Am Chem Soc 1962;84:3597–8.

    Google Scholar 

  48. Heidelberger C, King DH. Trifluorothymidine. Pharmacol Ther 1979;6:427–42.

    Google Scholar 

  49. Heidelberger C, Danenberg PV, Moran RG. Fluorinated pyrimidines and their nucleosides. Adv Enzymol 1983;54:57–119.

    Google Scholar 

  50. Carmine AA, Brogden RN, Heel RC, Speight TM, Avery GS. Trifluridine: a review of its antiviral activity and therapeutic use in the topical treatment of viral eye infections. Drugs 1982;23:329–53.

    PubMed  Google Scholar 

  51. Kaufman HE, Heidelberger C. Therapeutic antiviral action of 6-trifluoromethyl-2′-deoxyuridine in herpes simplex keratitis. Science 1964;145:585–6.

    PubMed  Google Scholar 

  52. Cassiman JJ, De Clercq E, Jones AS, Walker RT, Van Den Berghe H. Sister chromatid exchange induced by antiherpes drugs. BMJ 1981;283:817–8.

    PubMed  Google Scholar 

  53. Pietrzykowska I, Shugar D. Studies on bacteriophage and bacteriophage DNA containing 5-ethyluracil or 5-bromouracil in place of thymine. Acta Biochim Polon 1967;14:169–81.

    PubMed  Google Scholar 

  54. Świerkowski M, Shugar D. A nonmutagenic thymidine analog with antiviral activity. 5-Ethyldeoxyuridine. J Med Chem 1969;12:533–4.

    PubMed  Google Scholar 

  55. Remin M, Ekiel I, Shugar D. Proton magnetic resonance study of solution conformation of theα andβ anomers of 5-ethyl-2′-deoxyuridine. Eur J Biochem 1975;75:197–206.

    Google Scholar 

  56. Kulikowski T, Shugar D. 5-Alkylpyrimidine nucleosides. Preparation and properties of 5-ethyl-2′-deoxycytidine and related nucleosides. J Med Chem 1974;17:269–73.

    PubMed  Google Scholar 

  57. Gauri KK, Pflughaupt KW, Müller R. Synthese und photochemische Eigenschaften von 1-(2′-Desoxy-beta-D-ribofuranosyl)-(4-3H)-5-äthyluracil. Z Naturforsch 1969;24B:833–6.

    Google Scholar 

  58. De Clercq E, Shugar D. Antiviral activity of 5-ethyl pyrimidine deoxynucleosides. Biochem Pharmacol 1975;24:1073–8.

    PubMed  Google Scholar 

  59. De Clercq E, Kulikowski T, Shugar D. The 5′-monophosphates of 5-propyl- and 5-ethyl-2′-deoxyuridine do not inhibit the replication of deoxythymidine kinase deficient (TK) mutants of herpes simplex virus. Biochem Pharmacol 1980;29:2883–5.

    PubMed  Google Scholar 

  60. De Clercq E, Bernaerts R. Mechanism of antiviral activity of 5-ethyl-2′-deoxyuridine. Nucleosides Nucleotides 1987;6:421–2.

    Google Scholar 

  61. Schinazi RF, Scott RT, Peters J, Rice V, Nahmias AJ. Antiviral activity of 5-ethyl-2′-deoxyuridine against herpes simplex viruses in cell culture, mice and guinea pigs. Antimicrob Agents Chemother 1985;28:552–60.

    PubMed  Google Scholar 

  62. Guari KK, Malorny G, Riehm E. 5-Äthyl-2′-desoxyuridin (ÄDU) auf die Regeneration der experimentell geschädigten Cornea. Graefer Arch Klin Ophthalmol 1970;179:287–93.

    Google Scholar 

  63. Kunkel HA, Gauri KK, Malorny G. Biophysik. Keine Mutationsauslösung durch 5-Äthyl-2′-desoxyuridin (ÄDU) beiDrosophila melanogaster. 1968;5:88–90.

    Google Scholar 

  64. Gauri KK, Shif I, Wolford RG. Failure of 5-ethyl-2′-deoxyuridine to induce oncogenic RNA viruses in Fisher rat embryo cells and in Balb/3T3 mouse cells. Biochem Pharmacol 1976;25;1809–10.

    PubMed  Google Scholar 

  65. Walker RT, Barr PJ, De Clercq E, Descamps J, Jones AS, Serafinowski P. The synthesis and properties of some antiviral nucleosides. Nucleic Acids Res Spec Publ 1978;4:103–6.

    Google Scholar 

  66. De Clercq E, Descamps J, De Somer P, Barr PJ, Jones AS, Walker RT. (E)-5-(2-bromovinyl)-2′-deoxyuridine, a potent and selective antiherpes agent. Proc Natl Acad Sci USA 1979;76:2947–51.

    PubMed  Google Scholar 

  67. Jones AS, Rahim SG, Walker RT, De Clercq E. Synthesis and antiviral properties of (2)-5-(2-bromovinyl)-2′-deoxyuridine. J Med Chem 1981;24:759–60.

    PubMed  Google Scholar 

  68. Reefschläger J, Bärwolff D, Herrmann G, Langen P. Antiherpes activity of some novel analogues of (E)-5-(2-bromovinyl)-2′-deoxyuridine (E-BrVUdR) in two different cell lines. Acta Virol 1984;28:1–10.

    PubMed  Google Scholar 

  69. De Clercq E, Verhelst G, Descamps J, Bergström DE. Differential inhibition of herpes simplex viruses, type 1 (HSV-1) and type 2 (HSV-2), by (E)-5-(2-X-vinyl)-2′-deoxyuridines. Acta Microb Acad Sci Hung 1981;28:307–12.

    Google Scholar 

  70. Fyfe JA. Differential phosphorylation of (E)-5-(2-bromovinyl)-2′-deoxyuridine monophosphate by thymidylate kinases from herpes simplex viruses types 1 and 2 and varicella zoster virus. Mol Pharmacol 1982;21:432–7.

    PubMed  Google Scholar 

  71. Allaudeen HS, Kozarich JW, Bertino JR, De Clercq E. On the mechanism of selective inhibition of herpes virus replication by (E)-5-(2-bromovinyl)-2′-deoxyuridine. Proc Natl Acad Sci USA 1981;78:2698–702.

    PubMed  Google Scholar 

  72. Mancini WR, De Clercq E, Prusoff WH. The relationship between incorporation of (E)-5-(2-bromovinyl)-2′-deoxyuridine into herpes simplex virus type 1 DNA with virus infectivity and DNA integrity. J Biol Chem 1983;258:792–5.

    PubMed  Google Scholar 

  73. Balzarini J, Bernaerts R, Verbruggen A, De Clercq E. (E)-5-(2-iodovinyl)-2′-deoxyuridine and its carbocyclic analogue into DNA of herpes simplex virus type 1 -infected cells in the antiviral effects of these compounds. Mol Pharmacol 1990;37:402–7.

    PubMed  Google Scholar 

  74. Sági J, Czuppon A, Kajtar M, Szabolcs A, Szemzö A, Ötvos L. Modified polynucleotides VI. Properties of a synthetic DNA containing the anti-herpes agent (E)-5-(2-bromovinyl)-2′-deoxyuridine. Nucleic Acids Res 1982;10:6051–66.

    PubMed  Google Scholar 

  75. Barr PJ, Oppenheimer NJ, Santi DV. Thymidylate synthetase-catalyzed conversions of (E)-5-(2-bromovinyl)-2′-deoxyuridylate. J Biol Chem 1983;258:13627–31.

    PubMed  Google Scholar 

  76. Veres Z, Szabolc A, Szinai I, Dénes G, Jeney A. Enzymatic cleavage of 5-substituted 2′-deoxyuridines by pyrimidine nudeoside phosphorylases. Biochem Pharmacol 1986;35:1057–9.

    PubMed  Google Scholar 

  77. Desgranges C, Razaka G, Rabaud M, Bricaud H, Balzarini J, De Clercq E. Phosphorolysis of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and other 5-substituted 2′-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets. Biochem Pharmacol 1989;32:3583–90.

    Google Scholar 

  78. Machida H, Sakata S, Kuninaka A, Yoshino H, Nakayama C, Saneyoshi M.In vitro antiherpes viral activity of 5-alkyl derivatives of 1-β-D-arabinofuranosyluracil. Antimicrob Agents Chemother 1979;16:158–63.

    PubMed  Google Scholar 

  79. Kulikowski T, Zawadzki Z, Shugar D, Descamps J, De Clercq E. Synthesis and antiviral activities of arabinofuranosyl-5-ethylpyrimidine nucleosides. Selective antiherpes activity of 1-(β-D-arabinofuranosyl)-5-ethyluracil. J Med Chem 1979;22:647–53.

    PubMed  Google Scholar 

  80. Machida H, Sakata S, Kuninaka A, Yoshino H. Antiherpesviral and anticellular effects of 1-beta-D-arabinofuranosyl-E-5-(2-halogenovinyl)uracils. Antimicrob Agents Chemother 1981;20:47–52.

    PubMed  Google Scholar 

  81. De Clercq E, Busson R, Colla L, Descamps J, Balzarini J, Vanderhaege H. Antiviral activity of sugar-modified derivatives of (E)-5-(2-bromovinyl)-2′-deoxyuridine. In: Periti P, Grassi GG, editors. Current Chemotherapy and Immunotherapy. Washington: American Society for Microbiology, 1982:1062–4.

    Google Scholar 

  82. Machida H, Kuninaka A, Yoshino H, Ikeda K, Mizuno Y. Antiherpes viral activity and inhibitory action on cell growth of 5-alkenyl derivatives of 1-beta-D-arabinofuranosyluracil. Antimicrob Agents Chemother 1980;17:1030–1.

    PubMed  Google Scholar 

  83. Shealy YF, O'Dell CA, Shannon WM, Arnett G. Carbocyclic analogues of 5-substituted uracil nucleosides: synthesis and antiviral activity. J Med Chem 1983;26:156–61.

    PubMed  Google Scholar 

  84. Shealy YF, O'Dell CA, Arnett G, Shannon WM. Synthesis and antiviral activity of the carbocyclic analogues of 5-ethyl-2′-deoxyuridine and 5-ethynyl-2′-deoxyuridine. J Med Chem 1986;29:79–84.

    PubMed  Google Scholar 

  85. Maruyama T, Hanai Y, Sato Y, Snoeck R, Andrei G, Hosoya M, et al. Synthesis and antiviral activity of carbocyclic oxetanocin analogues (C-OXT-A, C-OXT-G) and related compounds. II. Chem Pharm Bull 1993;41:516–21.

    PubMed  Google Scholar 

  86. Balzarini J, De Clercq E, Baumgartner H, Bodenteich M, Griengl H. Carbocyclic 5-iodo-2′-deoxyuridine (C-IDU) and carbocyclic (E)-5-(2-bromovinyl)-2′-deoxyuridine (CBVDU) as unique examples of chiral molecules where the two enantiometric forms are biologically active: interaction of the (+) and (−) enantiomers of C-IDU and C-BVDU with the thymidine kinase of herpes simplex virus type 1. Mol Pharmacol 1990;37:395–401.

    PubMed  Google Scholar 

  87. Yokota T, Konno K, Mori S, Shigeta S, Kumagai M, Watanabe Y, et al. Mechanism of selective inhibition of varicella zoster virus replication by 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyluracil). Mol Pharmacol 1989;36:312–6.

    PubMed  Google Scholar 

  88. Bario JR, Bryant JD, Keyser GE. A direct method for the preparation of 2-hydroxymethyl derivatives of guanine, adenine and cytosine. J Med Chem 1980;23:572–4.

    PubMed  Google Scholar 

  89. Schaffer HJ, Beauchamp L, De Miranda P, Elion GB, Bauer DJ, Collins P. 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 1978;272:583–5.

    PubMed  Google Scholar 

  90. De Clercq E. Selective antiherpes agents. Trends Pharmacol Sci 1982;3;492–5.

    Google Scholar 

  91. Derse P, Cheng YC, Furman PA, St Claire MH, Elion GB. Inhibition of purified human and herpes simplex virusinduced DNA polymerases by 9-(2-hydroxyethoxymethyl)guanine triphosphate. J Biol Chem 1981;256:11447–51.

    PubMed  Google Scholar 

  92. Collins P, Bauer DJ. The activityin vitro against herpes virus of 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine), a new antiviral agent. J Antimicrob Chemother 1979;5:431–6.

    PubMed  Google Scholar 

  93. Crumpacker CS, Schnipper LE, Zaia JA, Levin MJ. Growth inhibition by acycloguanosine of herpes viruses isolated from human infections. Antimicrob Agents Chemother 1979;15:642–5.

    PubMed  Google Scholar 

  94. Biron KK, Elion GB.In vitro susceptibility of varicella zoster virus to acyclovir. Antimicrob Agents Chemother 1980;18:443–7.

    PubMed  Google Scholar 

  95. Mindel A, Kinghorn G, Alison-Jones E, Wodee P, Barton I, Faherty A, et al. Treatment of first-attack genital herpesacyclovir versus inosine pranobex. Lancet 1987;1:1171–3.

    PubMed  Google Scholar 

  96. Straus SE, Takiff HE, Seidlin M, Bachrach S, Lininger L, Di Giovanna JJ, et al. Suppression of frequently recurring genital herpes. A placebo-controlled double blind trial of oral acyclovir. N Engl J Med 1984;310:1545–50.

    PubMed  Google Scholar 

  97. De Clercq E. Recent advances in the search for selective antiviral agents. Adv Drug Res 1988;17:1–59.

    Google Scholar 

  98. Field AK, Davies ME, De Witt C, Perry HC, Liou R, Germershausen J, et al. Hydroxy-1-(hydroxymethyl)ethoxy-methyl-guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci USA 1983;80:4139–43.

    PubMed  Google Scholar 

  99. Freitas VR, Smee DF, Chernow M, Boehme R, Matthews TR. Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegalovirus. Antimicrob Agents Chemother 1985;28:240–5.

    PubMed  Google Scholar 

  100. Lin JC, Smith MC, Pagano JS. Prolonged inhibitory effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine against replication of Epstein-Barr virus. J Virol 1984;50:50–5.

    PubMed  Google Scholar 

  101. Cheng YC, Grill SP, Dutschman GE, Nakayama K, Bastow KF. Metabolism of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a new anti-herpes virus compound, in herpes simplex virus-infected cells. J Biol Chem 1983;258:12460–4.

    PubMed  Google Scholar 

  102. Biron KK, Stanat SC, Sorrell JB, Fyfe JA, Keller PM, Lambe CU, et al. Metabolic activation of the nucleoside analog 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human diploid fibroblasts infected with human cytomegalovirus. Proc Natl Acad Sei USA 1985;82:2473–7.

    Google Scholar 

  103. Estes JE, Huang ES. Stimulation of cellular thymidine kinases by human cytomegalovirus. J Virol 1976;24:13–21.

    Google Scholar 

  104. Fyfe JA, Keller PM, Furman PA, Miller RL, Elion GB. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J Biol Chem 1978;253:8721–7.

    PubMed  Google Scholar 

  105. Larsson A, Stenberg K, Ericson AC, Haglund U, Yisak WA, Johanson NG, et al. Mode of action, toxicity, pharmacokinetics, and efficacy of some new antiherpes virus guanosine analogs related to buciclovir. Antimicrob Agents Chemother 1986;30:598–605.

    PubMed  Google Scholar 

  106. Harnden MR, Jarvest RL, Bacon TH, Boyd MR. Synthesis and antiviral activity of 9-[4-hydroxy-3(hydroxymethyl)-but-1-yl] purines. J Med Chem 1987;30:1636–42.

    PubMed  Google Scholar 

  107. Boyd MR, Bacon TH, Sutton D, Cole M. Antiherpes virus activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) in cell culture. Antimicrob Agents Chemother 1987;31:1238–42.

    PubMed  Google Scholar 

  108. Akesson-Johansson A, Harmenberg J, Wahren B, Linde A. Inhibition of human herpes virus 6 replication by [4-hydroxy-2-(hydroxymethyl)-butyl]guanine (2HM-HBG) and other antiviral compounds. Antimicrob Agents Chemother 1990;34:2417–9.

    PubMed  Google Scholar 

  109. Stenberg K, Larsson A, Datema R. Metabolism and mode of action of (R)-9-(3,4-dihydroxybutyl) guanine in herpes simplex virus infected Vero cells, J Biol Chem 1986;261:2134–9.

    PubMed  Google Scholar 

  110. Stenberg K, Lundstrom M, Olofson S, Datema R. Incorporation into nucleic acids of the antiherpes guanosine analog buciclovir and effects on DNA protein synthesis. Biochem Pharmacol 1988;37:1925–31.

    PubMed  Google Scholar 

  111. Field AK, Tuomari AV, McGeever-Rubin B, Terry BJ, Mazina KE, Haffey ML, et al. (±)-(1α,2β,3α)-9-[2,3-bis-(hydroxymethylcyclobutyl]guanine [(±)-BHCG or SQ 33054] a potent and selective inhibitor of herpes viruses. Antiviral Res 1990;13:41–52.

    PubMed  Google Scholar 

  112. Hayashi S, Norbeck DW, Rosenbrook W, Fine RL, Matsukara M, Plattner JJ, et al. Cyclobut-A and cyclobut-G, carbocyclic oxetanocin analogs that inhibit the replication of human immunodeficiency virus in T cells and monocytes and macrophagesin vitro. Antimicrob Agents Chemother 1990;34:287–94.

    PubMed  Google Scholar 

  113. Norbeck DW, Kern E, Hayashi S, Rosenbrook W, Sham H, Herrin T, et al. Cyclobut-A and cyclobut-G: broad-spectrum antiviral agents with potential utility for the therapy of AIDS. J Med Chem 1990;33:1281–85.

    PubMed  Google Scholar 

  114. Nishiyama Y, Yamamoto N, Takahashi K, Shimada N. Selective inhibition of human cytomegalovirus replication by novel nucleoside, oxetanocin G. Antimicrob Agents Chemother 1988;32:1053–6.

    PubMed  Google Scholar 

  115. Harnden MR, Bailey S, Boyd MR, Cole M, Jarvest RL, Wyatt PG. New purine derivatives with selective antiviral activity. In: Leeming PR, editor. Topics in medicinal chemistry. Proceedings of 4th SCI-RSC Medicinal Chemistry Symposium; 1987 Sep 6–9; Cambridge, England. Cambridge: Royal Society of Chemistry, 1987:214–44.

    Google Scholar 

  116. Harnden MR. Penciclovir and famciclovir, selective antiherpes agents. In: Shugar D, Rode W, Borowski E, editors. Molecular aspects of chemotherapy. Proceedings of the Third International Symposium on Molecular Aspects of Chemotherapy; 1991 Jun 19–21; Gdańsk. Warszawa: Springer-Verlag-PWN, 1992;219–30.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Inslitute of Biochemistry and Biophysics, Polish Academy of Sciences, 36 Rakowiecka St., 02-532, Warszawa, Poland

    T. Kulikowski

Authors
  1. T. Kulikowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kulikowski, T. Structure-activity relationships and conformational features of antiherpetic pyrimidine and purine nucleoside analogues. A review. Pharm World Sci 16, 127–138 (1994). https://doi.org/10.1007/BF01880663

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01880663

Keywords

Search

Navigation