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L-Nucleosides as Chemotherapeutic Agents

  • Giuseppe Gumina
  • Youhoon Chong
  • Chung K. Chu
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Nucleoside analogs have been a major class of chemotherapeutic agents. Currently, more than 30 commercially available antiviral and antitumor nucleosides and nucleoside analogs are available. Among nucleoside analogs, nonnatural L-enantiomers have been particularly interesting. The most notable example is lamivudine, which has been playing an important role in the treatment of human immunodeficiency virus and hepatitis B virus infections. The reason for their high therapeutic potential is that, when biologically active, L-nucleosides have proven to possess favorable toxicological, chemical, and biochemical profiles, such as potency, low toxicity, and high metabolic stability. These characteristics have been the key factors in their success as drugs. Currently, two L-nucleosides, lamivudine and emtricitabine, are available for the treatment of human immunodeficiency virus and hepatitis B virus infections, and several other analogs, such as clevudine and troxacitabine, are in advanced clinical trial development stages. Among these, troxacitabine, a true chain terminator, is the first L-nucleoside endowed with promising antitumor activity against leukemia as well as solid tumors. This chapter reviews the important L-nucleosides used in therapy as well as compounds in development.

Key Words

Anticancer agents antiviral agents deoxycytidine kinase L-nucleosides troxacitabine. 

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References

  1. 1.
    Mitsuya, H., Weinhold, K. J., Furman, P. A., et al. 3′-Azido-3′-deoxythimidine (BWA509U): 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. USA. 1985;82:7096–7100.PubMedCrossRefGoogle Scholar
  2. 2.
    Mitsuya, H., Broder, S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/limphadenopathy-associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides. Proc. Natl. Acad. Sci. USA. 1986;83:1911–1915.PubMedCrossRefGoogle Scholar
  3. 3.
    Lin, T.-S., Schinazi, R. R, Prusoff, W. H. Potent and selective in vitro activity of 3′-deoxythymidin-2′-ene (3′-deoxy-2′,3′-didehydrothymidine) against human immunodeficiency virus. Biochem. Pharm. 1987;36:2713–2718.PubMedCrossRefGoogle Scholar
  4. 4.
    Schinazi, R. R, Chu, C. K., Peck, A., et al. Activities of the four optical isomers of 2′,3′-dideoxy-3′-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob. Agents Chemother. 1992, 36, 672–676.PubMedGoogle Scholar
  5. 5.
    Dobkin J. F. Abacavir enters the clinic. Infect. Med. 1999;16:7–7.Google Scholar
  6. 6.
    Daluge, S. M., Good, S. S., Faletto, M. B., et al. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob. Agents Chemother. 1997;41:1082–1093.Google Scholar
  7. 7.
    Balzarini, J., Aquaro, S., Perno, C.-F., Witvrouw, M., Holy, A., De Clercq, E. Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodefi-ciency virus in different human cell systems. Biochem. Biophys. Res. Comm. 1996;219:337–341.PubMedCrossRefGoogle Scholar
  8. 8.
    Naesens, L., Balzarini, J., De Clercq, E. Therapeutic potential of PMEA as an antiviral drug. Med. Virol. 1994;4:147–159.CrossRefGoogle Scholar
  9. 9.
    De Clercq, E. Broad-spectrum anti-DNA virus and anti-retrovirus activity of phos-phonylmethoxyalkylpurine and pyrimidines. Biochem. Pharmacol. 1991;42:963–972.Google Scholar
  10. 10.
    Srinivas, R. V., Robbins, B. L., Connelly, M. C., Gong, Y.-R, Bischofberger, N., Fridland, A. Metabolism and in vitro antiretroviral activities of bis(pivaloy-loxymethyl) prodrugs of acyclic nucleoside phosphonates. Antimicrob. Agents Chemother. 1993;37:2247–2250.PubMedGoogle Scholar
  11. 11.
    Galban-Garcia, E., Vega-Sanchez, H., Gra-Oramas, B., et al. Efficacy of ribavirin in patients with chronic hepatitis B. J. Gastroenterol. 2000;35:347–352.CrossRefGoogle Scholar
  12. 12.
    Coates, J. A. V., Cammack, N., Jenkinson, H. J., et al. The separated enan-tiomers of 2′-deoxy-3′-thiacytidine (BCH-189) both inhibit human immunod-eficiency virus replication in vitro. Antimicrob. Agents Chemother. 1992;36:202–205.PubMedGoogle Scholar
  13. 13.
    Furman, P. A., Davis, M., Liotta, D. C., et al. The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (–) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FTC). Antimicrob. Agents Chemother. 1992;36:2686–2692.Google Scholar
  14. 14.
    Furman, P. A., Wilson, J. E., Reardon, J. E., Painter, G. R. The effect of absolute configuration on the anti-HIV and anti-HBV activity of nucleoside analogs. Antiviral Chem. Chemother. 1995;6:345–355.Google Scholar
  15. 15.
    Wang, P., Hong, J. H., Cooperwood, J. S., Chu, C.K. Recent advances in L-nucle-osides: chemistry and biology. Antiviral Res. 1998;40:19–44.PubMedCrossRefGoogle Scholar
  16. 16.
    Gumina, G., Song, G.-Y., Chu, C. K. L-Nucleosides as chemotherapeutic agents. FEMS Microb. Lett. 2001;202:9–15.Google Scholar
  17. 17.
    Gumina, G., Chong, Y., Choo, H., Song, G.-Y., Chu, C. K. L-Nucleosides: Antiviral activity and molecular mechanism. Curr. Top. Med. Chem. 2002;2:1065–1086.PubMedCrossRefGoogle Scholar
  18. 18.
    Smejkal, J., Sorm, F. Nucleic acid components + their analogs. 53. Preparation of 1-(2-deoxy-β-L-ribofuranosyl)thymine (L-thymidine). Collec. Czech. Chem. Commun. 1964;29:2809–2813.Google Scholar
  19. 19.
    Coates, J. A. V., Cammack, N., Jenkinson, H. J., et al. The separated enantiomers of 2′-deoxy-3′-thiacytidine (BCH-189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob. Agents Chemother. 1992;36:202–205.PubMedGoogle Scholar
  20. 20.
    Jarvis, B., Faulds, D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B. Drugs 1999;58:101–141.PubMedCrossRefGoogle Scholar
  21. 21.
    Chu, C. K., Beach, J. W., Jeong, L. S., et al. Enantiomeric synthesis of (+)-BCH-189-[(+)-(2S,5R)-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine] from D-Mannose and its anti-HIV activity. J. Org. Chem. 1991;56:6503–6505.CrossRefGoogle Scholar
  22. 22.
    Jeong, L. S., Alves, A. J., Carrigan, S. W., Kim, H. O., Beach, W., Chu, C.K. An efficient synthesis of enantiomeric ally pure (+)-(2S,5R)-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine [(+)-BCH-189] from D-galactose. Tetrahedron Lett. 1992;33:595–598.CrossRefGoogle Scholar
  23. 23.
    Beach, J. W., Jeong, L. S., Alves, A. J., et al. Synthesis of enantiomeric ally pure (2′R,5′S)-(-)-1-[2-(hydroxymethyl)oxathiolan-5-yl]-cytosine as a potent antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV). J. Org. Chem. 1992;57:2217–2219.CrossRefGoogle Scholar
  24. 24.
    Chang, C.-N., Doong, S.-L., Zhou, J. H., et al. Deoxycytidine deamination-resistant stereoisomer is the active form of (–)-2′,3′-dideoxy-3′-thiacytidine in the inhibition of hepatitis B virus replication. J. Biol. Chem. 1992;267:13,938–13,942.PubMedGoogle Scholar
  25. 25.
    Severini, A., Liu, X.-Y., Wilson, J. S., Tyrrell, D. L. J. Mechanism of inhibition of duck hepatitis B virus polymerase by (–)-β-L-2′,3′-dideoxy-3′-thiacytidine. Antimicrob. Agents Chemother. 1995;39:1430–1435.Google Scholar
  26. 26.
    Shewach, D. S., Liotta, D. C., Schinazi, R. F. Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2′-deoxycytidine kinase. Biochem. Pharmacol. 1993;45:1540–1543.Google Scholar
  27. 27.
    Hart, G. J., Orr, D. C., Penn, C. R., et al. Effects of (–)-2′-deoxy-3′-thiacytidine (3TC) 5′-triphosphate on human immunodeficiency virus reverse trancriptase and mammalian DNA polymerase ?, polymerase β, and polimerase γ. Antimicrob. Agents Chemother. 1992;36:1688–1694.Google Scholar
  28. 28.
    Lee, K., Chu, C. K. Molecular modeling approach to understanding the mode of action of L-Nucleosides as antiviral agents. Antimicrob. Agents Chemother. 2001;45:138–144.CrossRefGoogle Scholar
  29. 29.
    Sarafianos, S. G., Das, K., Clark, A. D., Jr., et al. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with β-branched amino acids. Proc. Natl. Acad. Sci. USA. 1999;96:10,027–10,032.PubMedCrossRefGoogle Scholar
  30. 30.
    Tisdale, M., Kemp, S. D., Parry, N. R., Larder, B. A. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc. Natl. Acad. Sci. USA. 1993;90:5653–5656.PubMedCrossRefGoogle Scholar
  31. 31.
    Stuyver, L. J., Locarnini, S. A., Lok, A., et al. Nomenclature for antiviral-resist-ant human hepatitis B virus mutations in the polymerase region. Hepatology 2001;33:751–757.PubMedCrossRefGoogle Scholar
  32. 32.
    Fu, L., Cheng, Y.-C. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TC) resistance. Biochem. Pharmacol. 1998;55:1567–1572.PubMedCrossRefGoogle Scholar
  33. 33.
    Fu, L., Liu, S.-H., Cheng, Y.-C. Sensitivity of L-(-)2′,3′-dideoxythiacytidine resistant hepatitis B virus to other antiviral nucleoside analogs. Biochem. Pharmacol. 1999;57:1351–1359.PubMedCrossRefGoogle Scholar
  34. 34.
    Chong, Y., Stuyver, L., Otto, M. J., Shinazi, R. F., Chu, C. K. Mechanism of antiviral activities of 3′-substituted L-Nucleosides against 3TC-resistant HBV polymerase: a molecular modelling approach. Antiviral Chem. Chemother. 2003;14:309–319.Google Scholar
  35. 35.
    Rusconi, S., De Pasquale, M. P., Milazzo, L., et al. In vitro effects of continuous pressure with zidovudine (ZDV) and lamivudine on a ZDV-resistant HIV-1 isolate. AIDS 1997;11:1406–1410.PubMedGoogle Scholar
  36. 36.
    Murray, L., Kelly, G. L., Deutsch, M., Wyble, C. Combivir® tablets (lamivudine/ zidovudine tablets). In: Physicians, Desk Reference. 55th ed. 2001, http://www.pdr.net, pp. 1365–1368.
  37. 37.
    Patick, A. K., Boritzki, T. J., Bloom, L. A. Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. Antimicrob. Agents Chemother. 1997;41:2159–2164.PubMedGoogle Scholar
  38. 38.
    Landers, M. B., Fraser, V. J. Antiviral chemoprophylaxis after occupational exposure to human immunodeficiency virus: why, when, where, and what. Am. J. Ophthal. 1997;124:234–239.PubMedGoogle Scholar
  39. 39.
    Notermans, D. W., Jurriaans, S., De Wolf, F., et al. Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. AIDS 1998;12:167–173.PubMedCrossRefGoogle Scholar
  40. 40.
    Yuen, G. Y., Lou, Y., Thompson, N., et al. Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption. J. Clin. Pharmacol. 2001;41:277–288.PubMedCrossRefGoogle Scholar
  41. 41.
    Schinazi, R. R, McMillan, A., Cannon, D., et al. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob. Agents Chemother. 1992;36:2423–2431.Google Scholar
  42. 42.
    Furman, P. A., Davis, M., Liotta, D. C., et al. The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob. Agents Chemother. 1992;36:2686–2692.PubMedGoogle Scholar
  43. 43.
    Schinazi, R. F., Boudinot, F. D., Ibrahim, S. S., Manning, C., McClure, H. M., Liotta, D.C. Pharmacokinetics and metabolism of racemic 2′,3′-dideoxy-5-fluoro-3′-thiacy-tidine in rhesus monkeys. Antimicrob. Agents Chemother. 1992;36:2432–2438.Google Scholar
  44. 44.
    Bridges, E. G., Dutschman, G. E., Gullen, E. A., Cheng, Y.-C. Favorable interaction of β-L-(-) nucleoside analogs with clinically approved anti-HIV nucleoside analogs for the treatment of human immunodeficiency virus. Biochem. Pharmacol. 1996;51:731–736.PubMedCrossRefGoogle Scholar
  45. 45.
    Bryant, M., Bridges, E. G., Placidi, L., et al. Antiviral L-nucleosides specific for hepatitis B virus infection. Antimicrob. Agents Chemother. 2001;45:229–235.PubMedCrossRefGoogle Scholar
  46. 46.
    Bridges, E. G., Juodawikis, A., Faraj, A., et al. Antiviral activity of β-L-thymidine and β-L-2′-deoxycytidine in the woodchuck model of chronic hepatitis B infection. Antiviral Res. 2000;46:91–91.CrossRefGoogle Scholar
  47. 47.
    Chong, Y., Chu, C. K. Efficient synthesis of 2-deoxy-L-erithro-pentose (2-deoxy-L-ribose) from L-arabinose. Carbohydr. Res. 2002;337:397–402.PubMedCrossRefGoogle Scholar
  48. 48.
    Fujimori, S., Iwanami, N., Hashimoto, Y., Shudo, K. A. Convenient and stereo-selective synthesis of 2′-deoxy-β-L-ribonucleosides. Nucleosides Nucleotides 1992;11:341–349.CrossRefGoogle Scholar
  49. 49.
    Robins, M., Khwaja, T. A., Robins, R. K. Purine nucleosides. XXIX. The synthe-sis of 2′-deoxy-L-adenosine and 2′-deoxy-L-guanosine and their ? anomers. J. Org. Chem. 1970;35:636–639.PubMedCrossRefGoogle Scholar
  50. 50.
    Abbruzzese, J. L., Schmidt, S., Raber, M. N., et al. Phase I trial of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-methyluracil (FMAU) terminated by severe neurologic toxicity. Invest. New Drugs 1989;7:195–201.PubMedCrossRefGoogle Scholar
  51. 51.
    Chu, C. K., Ma, T. W., Shanmuganathan, K., et al. Use of 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus. Antimicrob. Agents Chemother. 1995;39:979–981.PubMedGoogle Scholar
  52. 52.
    Pai, S. B., Liu, S. H., Zhu, Y. L., Chu, C. K., Cheng, Y. C. Inhibition of hepatitis B virus: a novel L-nucleoside, 2′-fluoro-5-methyl-β-L-arabinofuranosyl uracil. Antimicrob. Agents Chemother. 1996;40:380–386.Google Scholar
  53. 53.
    Yao, G.-Q., Liu, S. H., Chou, E., Kukhanova, M., Chu, C. K., Cheng, Y. C. Inhibition of Epstein-Barr virus replication by a novel L-nucleoside, 2′-fluoro-5-methyl-β-L-arabinofuranosyl uracil. Biochem. Pharm. 1996;51:941–947.PubMedCrossRefGoogle Scholar
  54. 54.
    Du, J., Choi, Y., Lee, K., Chun, B. K., Hong, J. H., Chu, C. K. A practical synthesis of L-FMAU from L-arabinose. Nucleosides Nucleotides 1999;18:187–195.PubMedCrossRefGoogle Scholar
  55. 55.
    Ma, T., Pai, S. B., Zhu, Y. L., et al. Structure-activity relationships of 1-(2-deoxy-2-fluoro-β-L-arabinofuranosyl)pyrimidine nucleosides as anti-hepatitis B virus agents. J. Med. Chem. 1996;39:2835–2843.PubMedCrossRefGoogle Scholar
  56. 56.
    Liu, S.-H., Grove, K. L., Cheng, Y.-C. Unique metabolism of a novel antiviral L-nucleoside analog, 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil: a substrate for both thymidine kinase and deoxycytidine kinase. Antimicrob. Agents Chemother. 1998;42;833–839.PubMedGoogle Scholar
  57. 57.
    Kukhanova, M., Lin, Z.-Y., Yas-co, M., Cheng, Y.-C. Unique inhibitory effect of 1-(2′-deoxy-2′-fluoro-β-L-arabinofuranosyl)-5-methyluracil 5′-triphosphate on Epstein-Barr virus and human DNA polymerase. Biochem. Pharmacol. 1998;55:1181–1187.PubMedCrossRefGoogle Scholar
  58. 58.
    Chu, C. K., Boudinot, F. D., Peek, S. R, et al. Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent. In: Schinazi, R F., Sommadossi, J.-P. and Thomas, H. C., eds., Therapies for Viral Hepatitis. Vol. 32. UK: International Medical Press;1999, pp. 303–312.Google Scholar
  59. 59.
    Aguesse-Germon, S., Liu, S.-H., Chevallier, M., et al. Inhibitory effect of 2′-fluoro-5-methyl-β-L-arabinofuranosyl-uracil on duck hepatitis B virus replication. Antimicrob. Agents Chemother. 1998;42:369–376.Google Scholar
  60. 60.
    Peek, S. F., Cote, P. J., Jacob, J. R., et al. Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-β,L-arabinofuranosyl)uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax). Hepatology 2001;33:254–266.PubMedCrossRefGoogle Scholar
  61. 61.
    Chu, C. K., Boudinot, F. D., Peek, S. F., et al. Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent. Antivir. Ther. 1998, 3(suppl. 3), 113–121.PubMedGoogle Scholar
  62. 62.
    Gumina, G., Song, G.-Y., Chu, C. K. Advances in antiviral agents for hepatitis B virus. Antiviral Chem. Chemother. 2001;12:89–112.Google Scholar
  63. 63.
    Zhu, Y., Yamamoto, T., Cullen, J., et al. Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis. J. Virol. 2001;75:311–322.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee, K., Choi, Y., Gullen, E., et al. Synthesis and anti-HIV and anti-HBV activities of 2′-fluoro-2′,3′-unsaturated L-nucleosides. J. Med. Chem. 1999;42:1320–1328.PubMedCrossRefGoogle Scholar
  65. 65.
    Pai, S. B., Liotta, D. C., Chu, C. K., Schinazi, R. F. Inhibition of hepatitis B virus by novel, 2′-fluoro-2′,3′-unsaturated D-and L-nucleosides. Abstracts of Papers, Third International Conference on Therapies for Viral Hepatitis, Maui, HI. 1999, Abstract 125.Google Scholar
  66. 66.
    Pai, S. B., Chu, C. K., Liotta, D. C., Schinazi, R. F. 2′-Fluoro-2′,3′-unsaturated nucleosides as selective antivirals against hepatitis B virus. Antiviral Ther. 2000, 5(suppl. 1), B66–B66.Google Scholar
  67. 67.
    Lee, K., Choi, Y., Gumina, G., Zhou, W., Schinazi, R. F., Chu, C. K. Structure-activity relationships of 2′-fluoro-2′,3′-unsaturated D-nucleosides as anti-HIV-1 agents. J. Med. Chem. 2002;45:1313–1320.PubMedCrossRefGoogle Scholar
  68. 68.
    Gosselin, G., Boudou, V., Griffon, J.-F., et al. New unnatural L-nucleoside enan-tiomers: from their stereospecific synthesis to their biological activities. Nucleosides Nucleotides, 1997;16:1389–1398.CrossRefGoogle Scholar
  69. 69.
    Lin, T.-S., Luo, M.-Z., Liu, M.-C., et al. Design and synthesis of 2′,3′-dideoxy-2′,3′-didehydro-β-L-cytidine (β-L-d4C) and 2′,3′-dideoxy-2′,3′-didehydro-β-L-5-fluorocytidine (β-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human immunodeficiency virus (HIV) in vitro. J. Med. Chem. 1997;39:1757–1759.CrossRefGoogle Scholar
  70. 70.
    Le Guerhier F., Pichoud, C., Guerret, S., et al. Characterization of the antiviral effect of and 2′,3′-dideoxy-2′,3′didehydro-β-L-5-fluorocytidine in the duck hepatitis B virus infection model. Antimicrob. Agents Chemother. 2000;44:111–122.PubMedCrossRefGoogle Scholar
  71. 71.
    Dutschman, G. E., Bridges, E. G., Liu, S.-H., et al. Metabolism of 2′,3′-dideoxy-2′,3′-didehydro-β-L-(-)-5-fluorocytidine and its activity in combination with clinically approved anti-human immunodeficiency virus β-D-(+) nucleoside analogs in vitro. Antimicrob. Agents Chemother. 1998;42:1799–1804.PubMedGoogle Scholar
  72. 72.
    Kukhanova, M., Li, X., Chen, S.-H., et al. Interaction of β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluoro-CTP with human immunodeficiency virus-1 reverse transcriptase and human DNA polymerases: Implication for human immunodeficiency virus drug design. Mol. Pharmacol. 1998;53:801–807.PubMedGoogle Scholar
  73. 73.
    Zhu, Y.-L., Dutschman, G. E., Liu, S.-H., Bridges, E. G., Cheng, Y.-C. Anti-hepatitis B virus activity and metabolism of 2′,3′-dideoxy-2′,3′-didehydro-β-L-(-)-5-fluorocytidine. Antimicrob. Agents Chemother. 1998;42:1805–1810.PubMedGoogle Scholar
  74. 74.
    Le Guehier, F., Pichoud, C., Jamard, C., et al. Antiviral activity of β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine in woodchucks chronically infected with wood-chuck hepatitis virus. Antimicrob. Agents Chemother. 2001;45:1065–1077.CrossRefGoogle Scholar
  75. 75.
    Lin, J.-S., Kira, T., Gullen, E., et al. Structure-activity relationships of L-dioxolane uracil nucleosides as anti-Epstein Barr virus agents. J. Med. Chem. 1999;42:2212–2217.PubMedCrossRefGoogle Scholar
  76. 76.
    Kira, T., Grill, S. P., Dutschman, G. E., et al. Anti-Epstein-Barr virus (EBV) activity of-L-5-iododioxolane uracil is dependent on EBV thymidine kinase. Antimicrob. Agents Chemother. 2000;44:3278–3284.CrossRefGoogle Scholar
  77. 77.
    Kim, H. O., Ahn, S. K., Alves, A. J., et al. Asymmetric synthesis of 1,3-dioxolane pyrimidine nucleosides and their anti-HIV activity. J. Med. Chem. 1992;35:1987–1995.PubMedCrossRefGoogle Scholar
  78. 78.
    Kim, H. O., Schinazi, R. E, Nampalli, S., et al. 1,3-Dioxolanylpurine nucleosides (2R, 4R) and (2R, 4S) with selective anti-HIV activity in human lymphocytes. J. Med. Chem. 1993;36:30–37.PubMedCrossRefGoogle Scholar
  79. 79.
    Kim, H. O., Schinazi, R. E, Shanmuganathan, K., et al. L-β-(2S,4S)-and L-?-(2S,4S)-dioxolanyl nucleosides as potential anti-HIV agents: asymmetric synthesis and structure-activity relationships. J. Med. Chem. 1993;36:519–528.PubMedCrossRefGoogle Scholar
  80. 80.
    Kim, H. O., Shanmuganathan, S., Alves, A. J., et al. Potent anti-HIV and anti-HBV activities of (-)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric syntheses. Tetrahedron Lett. 1992;33:6899–6902.CrossRefGoogle Scholar
  81. 81.
    Grove, K. L., Guo, X., Liu, S. H., Kukhanova, M., Chu, C. K., Cheng, C.-Y. β-L-(-)-Dioxolane cytidine (β-L-(-)-OddC) as a potent compound for the treatment of cancer. Nucleosides Nucleotides 1997;16:1229–1233.CrossRefGoogle Scholar
  82. 82.
    Grove, K. L., Guo, X., Liu, S. H., Gao, Z. L., Chu, C. K., Cheng, Y.-C. Anticancer activity of β-L-dioxolane cytidine, a novel nucleoside analog with the unnatural L-configuration. Cancer Res. 1995;55:3008–3011.PubMedGoogle Scholar
  83. 83.
    Grove, K. L., Cheng, Y.-C. Uptake and metabolism of the new anticancer com-pound β-L-dioxolane cytidine in human prostate carcinoma DU-145 cells. Cancer Res. 1996;56:4187–4191.PubMedGoogle Scholar
  84. 84.
    Kim, H. O., Shanmuganathan, K., Alves, A. J., et al. Potent anti-HIV and anti-HBV activities of (-)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asym-metric synthesis. Tetrahedron Lett. 1992;33:6899–6902.CrossRefGoogle Scholar
  85. 85.
    Chou, K.-M., Kukhanova, M., Cheng, Y.-C. A novel action of human apurinic/apyrimidinic endonuclease. J. Biol. Chem. 2000;275:31,009–31,015.PubMedCrossRefGoogle Scholar
  86. 86.
    Moore, M., Belanger, K., Jolivet, J., Baker, S., Wainman, N. NCIC CTG IND 103: a phase I and pharmacokinetic (PK) study of the novel L-nucleoside analog troxacitabine (BCH-4556) given every 21 d. Eur. J. Cancer 1999;35:S284–S284.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Giuseppe Gumina
    • 1
  • Youhoon Chong
    • 2
  • Chung K. Chu
    • 3
  1. 1.Department of Pharmaceutical SciencesMedical University of South CarolinaCharleston
  2. 2.Department of Pharmaceutical and Biomedical SciencesCollege of Pharmacy, University of GeorgiaAthens
  3. 3.Department of Pharmaceutical and Biomedical SciencesCollege of Pharmacy, University of GeorgiaAthens

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