Allenols Derived from Nucleic Acid Bases — A New Class of Anti-HIV Agents: Chemistry and Biological Activity

  • Jiri Zemlicka


The last 15 years have witnessed a revival of interest in analogues of nucleosides following the discoveries that several of such compounds exhibit powerful antiviral effects. In this context, two compounds are of particular significance. The first of such analogues is acyclovir (1a, Zovirax) which was developed in the late seventies1 (Chart 1). Acyclovir (1a) is an analogue of 2′-deoxyguanosine of clinical importance as a drug for treatment of herpesvirus infections. The second compound is 3′-azido-3′-deoxythymidine (3b, AZT, zidovudine or Retrovir), an analogue of thymidine, and, until recently, the only approved drug for treatment of acquired immunodeficiency syndrome (AIDS). AZT (3b) was originally prepared in the sixties,2 its antiretroviral potential was recognized in the seventies,3 and it was developed as a therapeutic agent against AIDS in the eighties.4 Drugs 1a and 3b are examples of two structurally different classes of nucleoside analogues. Acyclovir (1a) belongs to a series of open-chain compounds derived by cleavage of at least one C-C bond or deletion of one or more carbon atoms of the sugar ring, whereas AZT (3b) comprises an intact furanose moiety.


Human Immunodeficiency Virus Nucleoside Analogue Adenosine Deaminase Adenosine Purine Nucleoside Phosphorylase Hydroxymethyl Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    H.J. Schaeffer, L. Beauchamp, P. de Miranda, G. B. Elion, D. J. Bauer, and P. Collins, 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group, Nature 272:583 (1978).PubMedCrossRefGoogle Scholar
  2. 2.
    J. P. Horwitz, J. Chua, and M. Noel, Nucleosides. V. The monomesylates of l-(2′-deoxy-ß-D-lyxofuranosyl)thymine, J. Org. Chem. 29:2076 (1964).CrossRefGoogle Scholar
  3. 3.
    W. Ostertag, G. Roesler, C. J. Krieg, J. Kind, T. Cole, T. Crozier, G. Gaedicke, G. Steinheider, N. Kluge, and S. Dube, Induction of endogenous virus and thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus, Proc. Natl. Acad. Sci. U.S.A. 71:4980 (1974).PubMedCrossRefGoogle Scholar
  4. 4.
    H. Mitsuya, K. J. Weinhold, P. A. Furman, M. H. St. Clair, S. W. Lehrman, R. C. Gallo, D. Bolognesi, D. W. Barry, and S. Broder, 3′-Azido-3′-deoxythymidine (BWA 5090): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphoadenopathy — associated virus in vitro, Proc. Natl. Acad. Sci. U.S.A. 82:7096 (1985).PubMedCrossRefGoogle Scholar
  5. 5.
    H. J. Schaeffer, S. Gurwara, R. Vince, and S. Bittner, Novel Substrate of Adenosine Deaminase, J. Med. Chem. 14:367(1971).PubMedCrossRefGoogle Scholar
  6. 6.
    J. L. Kelly, L. E. Kelsey, W. R. Hall, M. P. Krochmal, and H. J. Schaeffer, Pyrimidine acyclic nucleosides. l-[(2-Hydroxyethoxy)methyl]pyrimidines as candidate antivirals, J. Med. Chem. 24:753 (1981).CrossRefGoogle Scholar
  7. 7.
    H. Mitsuya, M. Matsukura, and S. Broder, Rapid in vitro systems for assessing activity of agents against HTLV-III/LAV, in: “AIDS, Modern Concepts and Therapeutic Challenges,” S. Broder, ed., Marcel Dekker, New York (1987), p. 303.Google Scholar
  8. 8.
    M. Baba, R. Pauwels, J. Balzarini, P. Herdewijn, and E. De Clercq, Selective inhibition of human immunodeficiency virus (HIV) by 3′-azido-2′,3′-dideoxyguanosine, Biochem. Biophys. Res. Commun. 145:1080 (1987).PubMedCrossRefGoogle Scholar
  9. 9.
    R. Dolin, Antiviral chemotherapy and chemoprophylaxis, Science 227:1296 (1985).PubMedCrossRefGoogle Scholar
  10. 10.
    H. Mitsuya, R. Yarchoan, and S. Broder, Molecular targets for AIDS therapy, Science 249:1533(1990).PubMedCrossRefGoogle Scholar
  11. 11.
    M. M. Mansuri, J. E. Starrett, Jr., I. Ghazzouli, M. J. M. Hitchcock, R. Z. Sterzycki, V. Brankovan, T.-S. Lin, E. M. August, W. H. Prusoff, J.-P. Sommadossi, and J. C. Martin, l-(2,3-Dideoxy-ß-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent, J. Med. Chem. 32:461 (1989).PubMedCrossRefGoogle Scholar
  12. 12.
    M. Baba, R. Pauwels, P. Herdewijn, E. De Clercq, J. Desmyter, and J. Vandeputte, Both 2′,3′-dideoxythymidine and its 2′,3′-unsaturated derivative (2′,3′-dideoxy-thymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro, Biochem. Biophys. Res. Commun. 142:128 (1987).PubMedCrossRefGoogle Scholar
  13. 13.
    R. Vince and M. Hua, Synthesis and anti-HIV activity of carbocyclic 2′,3′-didehydro-2′,3′-dideoxy 2,6-disubstituted purine nucleosides, J. Med. Chem. 33:17 (1990).PubMedCrossRefGoogle Scholar
  14. 14.
    V. E. Marquez and M.-I. Lim, Carbocyclic nucleosides, Med. Res. Rev.(London) 6:1 (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    A. Larsson, K. Stenberg, A.-C. Ericsson, U. Haglund, W. Yisak, N. G. Johansson, B. Öberg, and R. Datema, Mode of action, toxicity, pharmacokinetics, and efficacy of some antiherpes virus analogs related to buciclovir, Antimicrob. Agents Chemother. 30:598 (1986).PubMedCrossRefGoogle Scholar
  16. 16.
    M. Hua, P. M. Korkowski, and R. Vince, Synthesis and biological evaluation of acyclic neplanocin A analogues, J. Med. Chem. 30:198 (1987).PubMedCrossRefGoogle Scholar
  17. 17.
    S. Phadtare and J. Zemlicka, Synthesis and biological properties of 9-(trans-4-hydro-xy-2-buten-l-yl)adenine and guanine: Open-chain analogues of neplanocin A, J. Med. Chem. 30:437 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    D. R. Haines, C. K. H. Tseng, and V. E. Marquez, Synthesis and biological activity of unsaturated carboacyclic purine nucleoside analogues, J. Med. Chem. 30:943 (1987).PubMedCrossRefGoogle Scholar
  19. 19.
    D. R. Borcherding, S. Narayanan, M. Hasobe, J. G. McKee, B. T. Keller, and R. T. Borchardt, Potential inhibitors of S-adenosylmethionine-dependent methyltransfer-ases. 11. Molecular dissections of neplanocin A as potential inhibitors of S-adeno-sylhomocysteine hydrolase, J. Med. Chem. 31:1729 (1988).PubMedCrossRefGoogle Scholar
  20. 20.
    W. T. Ashton, L. C. Meurer, C. L. Cantone, A. K. Field, J. Hannah, J. D. Karkas, R. Liou, G. F. Patel, H. C. Perry, A. F. Wagner, E. Walton, and R. L. Tolman, Synthesis and antiherpetic activity of (±)-9-[[(Z)-2-(hydroxymethyl)cyclopropyl]-methyl]guanine and related compounds, J. Med. Chem. 31:2304 (1988).PubMedCrossRefGoogle Scholar
  21. 21.
    S. Phadtare, D. Kessel, and J. Zemlicka, Unsaturated nucleoside analogues: Synthesis and antitumor activity, Nucleosides Nucleotides 8:907 (1989).CrossRefGoogle Scholar
  22. 22.
    S. Phadtare, D. Kessel, T. H. Corbett, H. E. Renis, B. A. Court, and J. Zemlicka, Unsaturated and carbocyclic nucleoside analogues: Synthesis, antitumor, and antiviral activity, J. Med. Chem. 34:421 (1991).PubMedCrossRefGoogle Scholar
  23. 23.
    S. Phadtare and J. Zemlicka, Allenic derivatives of nucleic acid components and their transformation products: a new class of biologically active nucleoside analogues, Nucleic Acids Res., Symp. Ser. No. 18:25 (1987).Google Scholar
  24. 24.
    A. Larsson, S. Alenius, N.-G. Johansson, and B. Öberg, Antiherpetic activity and mechanism of action of 9-(4-hydroxybutyl)guanine, Antiviral Res. 3:77 (1983).PubMedCrossRefGoogle Scholar
  25. 25.
    S. Phadtare and J. Zemlicka, Nucleic acid derived allenols: Unusual analogues of nucleosides with antiretroviral activity, J. Am. Chem. Soc. 111:5925 (1989).CrossRefGoogle Scholar
  26. 26.
    H. Mitsuya and S. Broder, Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphoadenopathy-associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides, Proc. Natl. Acad. Sci. U.S.A. 83:1911 (1986).PubMedCrossRefGoogle Scholar
  27. 27.
    A. J. Hubert and H. Reimlinger, Base-catalysed prototropic isomerisations. Part II. The isomerisation of N-prop-2-ynyl heterocycles into N-substituted allenes and acetylenes, J. Chem. Soc. C:606 (1968).Google Scholar
  28. 28.
    D. Ranganathan, R. Rathi, K. Kesavan, and W. P. Singh, The demonstration of nor-mal O→N Claisen rearrangement in purines, Tetrahedron 42:43873 (1986).Google Scholar
  29. 29.
    A. A. Khorlin, I. P. Smirnov, S. V. Kochetkova, T. L. Tsilevich, I. L. Shchaveleva, B. P. Gottikh, and V. L. Florent′ev, Compounds similar to acyclovir. IV. Convenient method of synthesising adenallene, Bioorg. Khim. 15:530 (1989); English translation 15:291 (1990).PubMedGoogle Scholar
  30. 30.
    M. V. Kochetkova, A. V. Tsytovich, and B. I. Mitsner, A convenient approach to the synthesis of nucleic acid allene derivatives, possessing anti-HIV activity, Nucleic Acids Res., Symp. Ser. No. 24:233 (1991).Google Scholar
  31. 31.
    A. V. Tsytovich, M. V. Kochetkova, E. V. Kuznetsova, B. I. Mitsner, and V.I. Shvets, Acyclic nucleoside analogues. I. Development of allenic nucleoside derivatives synthesis, Bioorg. Khim. 17:1086 (1991) (in Russian).Google Scholar
  32. 32.
    S. Phadtare and J. Zemlicka, Synthesis of N1-(4-hydroxy-l,2-butadien-l-yl)thymine, an analogue of 3′-deoxythymidine, J. Org. Chem. 54:3675 (1989).CrossRefGoogle Scholar
  33. 33.
    S. Phadtare and J. Zemlicka, unpublished experiments.Google Scholar
  34. 34.
    S. Hayashi, S. Phadtare, J. Zemlicka, M. Matsukura, H. Mitsuya, and S. Broder, Adenallene and cytallene: Acyclic nucleoside analogues that inhibit replication and cytopathic effect of human immunodeficiency virus in vitro, Proc. Natl. Acad. Sci. U.S.A. 85:6127 (1988).PubMedCrossRefGoogle Scholar
  35. 35.
    S. Megati, Z. Goren, J. V. Silverton, J. Orlina, H. Nishimura, T. Shirasaki, H. Mitsuya, and J. Zemlicka, R-(-)-and S-(+)-adenallene: Synthesis, absolute configuration, antiretroviral effect, and enzymic deamination, J. Med. Chem. 35:4098 (1992).PubMedCrossRefGoogle Scholar
  36. 36.
    C. R. Noe, Chirale Lactole, II. Racematspaltung und enantioselektive Acetalisierung mit der 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl-Schutzgruppe, Chem. Ber. 115:1591 (1982).CrossRefGoogle Scholar
  37. 37.
    S. Phadtare and J. Zemlicka, Allenic derivatives of nucleic acid bases — new acyclic nucleoside analogues with antiretroviral activity, Nucleic Acids Res., Symp. Ser. No. 20:39 (1988).Google Scholar
  38. 38.
    P. Van Roey, E. W. Taylor, C. K. Chu, and R. F. Schinazi, Correlation of molecular conformation and activity of reverse transcriptase inhibitors, Ann. N. Y. Acad. Sci. 616:29 (1990).PubMedCrossRefGoogle Scholar
  39. 39.
    E. W. Taylor, P. Van Roey, R. F. Schinazi, and C. K. Chu, A stereochemical rationale for the activity of anti-HIV nucleosides, Antiviral Chem. Chemother. 1:163 (1990).Google Scholar
  40. 40.
    J. March, “Advanced Organic Chemistry”, McGraw-Hill, New York, 1977, p. 24.Google Scholar
  41. 41.
    W. Runge, Stereochemistry of allenes, in: “The Chemistry of the Allenes”, Vol. 3, S. R. Landor, ed., Academic Press, New York, 1982, p. 579.Google Scholar
  42. 42.
    N. N. H. Teng, M. S. Itzkowitz, and I. Tinoco, Jr., Calculation of the rotational strength of mononucleosides, J. Am. Chem. Soc. 93:6257 (1971).CrossRefGoogle Scholar
  43. 43.
    W. Runge, Spectroscopic properties of allenes, in: “The Chemistry of the Allenes”, Vol. 3, S. R. Landor, ed., Academic Press, New York, 1982, p. 777.Google Scholar
  44. 44.
    R. Gompper and U. Wolf, Synthesen und Reaktionen electronarmer Allene, Liebigs Ann. Chem. 1388 (1979).Google Scholar
  45. 45.
    S. Phadtare and J. Zemlicka, Synthesis of (Z)-and (E)-N9-(4-hydroxy-l-buten-l-yl)-adenine — new unsaturated analogues of adenosine, Tetrahedron Lett.31:43 (1990).CrossRefGoogle Scholar
  46. 46.
    J. R. Wiersig, A. N. H. Yeo, and C. Djerassi, Mass spectrometry in structural and stereochemical studies. 247. Electron-impact induced fragmentation of allenes, J. Am. Chem. Soc. 99:532 (1977).CrossRefGoogle Scholar
  47. 47.
    “The Chemistry of the Allenes11, Vol. 2, S. R. Landor, ed., 1982.Google Scholar
  48. 48.
    R. Engel, “Synthesis of Carbon-Phosphorus Bond”, CRC Press, Boca Raton, Florida, 1988, p. 21.Google Scholar
  49. 49.
    Ref. 48, p. 7.Google Scholar
  50. 50.
    “Nucleotide Analogues as Antiviral Agents”, ACS Symposium Series 401, J. C. Martin, ed., American Chemical Society, Washington, D. C, 1989.Google Scholar
  51. 51.
    S. Phadtare and J. Zemlicka, Unsaturated analogues of acyclic nucleoside phosphonates: An unusual Arbuzov reaction with unactivated triple bond, Nucleosides Nucleotides 10:275 (1991).CrossRefGoogle Scholar
  52. 52.
    S. Megati, S. Phadtare, and J. Zemlicka, Unsaturated phosphonates as acyclic nucleotide analogues. Anomalous Michaelis-Arbuzov and Michaelis-Becker reactions with multiple bond systems, J. Org. Chem. 57:2320 (1992).CrossRefGoogle Scholar
  53. 53.
    M. Huché and P. Cresson, Réactions sigmatropiques d’ordre (2,3) au niveau d’un atome de phosphore, Bull. Soc. Chim. Fr. No. 3-4:800 (1975).Google Scholar
  54. 54.
    A. J. Kirby and S. G. Warren, “The Organic Chemistry of Phosphorus”, Elsevier, New York, 1967, p.39.Google Scholar
  55. 55.
    H. Mitsuya and S. Broder, Strategies for antiviral therapy in AIDS, Nature325:773 (1987).PubMedCrossRefGoogle Scholar
  56. 56.
    S. Hayashi, S. Phadtare, J. Zemlicka, M. Matsukura, H. Mitsuya, and S. Broder, Adenallene and cytallene, two novel acyclic nucleoside derivatives active against human immunodeficiency virus (HIV) in T-cells and monocytes/macrophages in vitro: Further characterization of anti-viral and cytotoxic activity, in: “Mechanisms of Action and Therapeutic Applications of Biologicals in Cancer and Immune Deficiency Disorders”, Alan R. Liss, Inc., 1989, p. 371.Google Scholar
  57. 57.
    B. A. Larder, B. Chesebro, and D. D. Richman, Susceptibilities of zidovudine-susceptible and-resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay, Antimicrob. Agents Chemother. 34:436 (1990).PubMedCrossRefGoogle Scholar
  58. 58.
    M. M. Mansuri, V. Farina, J. E. Starrett, Jr., D. A. Benigni, V. Brankovan, and J. C. Martin, Preparation of the geometric isomers of DDC, DDA, D4C and D4T as potential anti-HIV agents, Bioorg. Med. Chem. Lett. 1:65(1991).CrossRefGoogle Scholar
  59. 59.
    S. Hayashi, M. Matsukura, H. Mitsuya, and S. Broder, unpublished results.Google Scholar
  60. 60.
    C.-H. Kim, V. E. Marquez, S. Broder, H. Mitsuya, and J. S. Driscoll, Potential AIDS drugs. 2′,3′-Dideoxycytidine analogues, J. Med. Chem. 30:862 (1987).PubMedCrossRefGoogle Scholar
  61. 61.
    R. Pauwels, M. Baba, J. Balzarini, P. Herdewijn, J. Desmyter, M. J. Robins, R. Zhou, D. Madej, and E. De Clercq, 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′-dideoxy-riboside, Biochem. Pharmacol. 37:1317 (1988).PubMedCrossRefGoogle Scholar
  62. 62.
    M. A. Johnson, G. Ahluwalia, M. C. Connelly, D. A. Cooney, S. Broder, D. G. Johns, and A. Fridland, Metabolic pathways for the activation of the antiretroviral agent 2′,3′-dideoxyadenosine in human lymphoid cells, J. Biol. Chem. 263:15354 (1988).PubMedGoogle Scholar
  63. 63.
    G. I. Birnbaum, M. Cygler, and D. Shugar, Conformational features of acyclonucleo-sides: structure of acyclovir, an antiherpes agent, Can. J. Chem. 62:2646 (1984).CrossRefGoogle Scholar
  64. 64.
    P. Van Roey, J. M. Salerno, C. K. Chu, and R. F. Schinazi, Correlation between preferred sugar conformation and activity of nucleoside analogues against human immunodeficiency virus, Proc. Natl. Acad. Sci. U.S.A. 86:3929 (1989).PubMedCrossRefGoogle Scholar
  65. 65.
    C. K.-H. Tseng, V. E. Marquez, G. W. A. Milne, R. J. Wysocki, Jr., H. Mitsuya, T. Shirasaki, and J. S. Driscoll, A ring-enlarged oxetanocin A analogue as an inhibitor of HIV infectivity, J. Med. Chem. 34:343 (1991).PubMedCrossRefGoogle Scholar
  66. 66.
    C. K. Chu, S. K. Ahn, H. O. Kim., J. W. Beach, A. J. Alves, L. S. Jeong, Q. Islam, P. Van Roey, and R. F. Schinazi, Asymmetric synthesis of enantiomerically pure (-)-(1′R,4′R)-dioxolane-thymine and its anti-HIV activity, Tetrahedron Lett. 32: 3791 (1991).CrossRefGoogle Scholar
  67. 67.
    Y.-C. Liaw, Y.-G. Gao, V. E. Marquez, and A. H.-J. Wang, Molecular structures of two new anti-HIV nucleoside analogs: 9-(2,3-dideoxy-2-fluoro-ß-D-rhreo-pento-furanosyl)adenine and 9-(2,3-dideoxy-2-fluoro-ß-D-rthreo-pentofuranosyl)hypo-xanthine, Nucleic Acids Res. 20:459 (1992).PubMedCrossRefGoogle Scholar
  68. 68.
    S. Eriksson, B. Kierdaszuk, B. Munch-Petersen, B. Öberg, and N. G. Johansson, Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogues, Biochem. Biophys. Res. Commun. 176:586 (1991).PubMedCrossRefGoogle Scholar
  69. 69.
    B. Kierdaszuk, C. Bohman, B. Ullman, and S. Eriksson, Substrate specificity of human deoxycytidine kinase toward antiviral 2′,3′-dideoxynucleoside analogues, Biochem. Pharmacol. 43:197 (1992).PubMedCrossRefGoogle Scholar
  70. 70.
    D. A. Cooney, G. Ahluwalia, H. Mitsuya, A. Fridland, M. Johnson, Z. Hao, M. Dalai, J. Balzarini, S. Broder, and D. G. Johns, Initial studies on the cellular pharmacology of 2′,3′-dideoxyadenosine, an inhibitor of HTLV-III infectivity, Biochem. Pharmacol. 36:1765 (1987).PubMedCrossRefGoogle Scholar
  71. 71.
    D. Kessel, unpublished results.Google Scholar
  72. 72.
    R. V. Joshi, D. Kessel, T. H. Corbett, and J. Zemlicka, Ynamines derived from nucleic acids bases: synthesis, reactivity and biological activity, J. Chem. Soc., Chem. Commun. No. 6:513 (1992).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Jiri Zemlicka
    • 1
  1. 1.Department of Chemistry, Michigan Cancer Foundation and Departments of Internal Medicine and BiochemistryWayne State University School of MedicineDetroitUSA

Personalised recommendations