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Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases

Nature Reviews Drug Discovery volume 12, pages 447–464 (2013)Cite this article

Subjects

Key Points

  • Nucleoside and nucleotide analogues are largely used in the treatment of cancer and viral infections.

  • A large number of novel compounds continue to be synthesized and evaluated both by academia and the pharmaceutical industry, which underlines the important interest in this family of drugs.

  • Different strategies are being used to develop new agents, such as pronucleotides and conjugates.

  • New agents are expected to have different resistance profiles compared to already approved agents.

  • New interferon-free regimens to cure hepatitis C virus infection are likely to contain a potent and pan-genotypic active nucleoside or nucleotide analogue. Two of these — sofosbuvir and mericitabine — are in Phase III clinical trials.

Abstract

Nucleoside analogues have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with cancer or viral infections. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Here, we review new nucleoside analogues and associated compounds that are currently in preclinical or clinical development for the treatment of cancer and viral infections, and that aim to provide increased response rates and reduced side effects. We also highlight the different approaches used in the development of these drugs and the potential of personalized therapy.

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Figure 1: General structural and chemical modifications of nucleoside and nucleotide analogues.
Figure 2: Mechanism of action of nucleoside analogues.
Figure 3: Chemical structures of representative anticancer and antiviral nucleoside and nucleotide analogues in development.
Figure 4: The pronucleotide strategy.

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References

  1. Elion, G. B. The quest for a cure. Annu. Rev. Pharmacol. Toxicol. 33, 1–23 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Elion, G. B. Acyclovir: discovery, mechanism of action, and selectivity. J. Med. Virol. Suppl. 1, 2–6 (1993).

    Article  Google Scholar 

  3. De Clercq, E. A 40-year journey in search of selective antiviral chemotherapy. Annu. Rev. Pharmacol. Toxicol. 51, 1–24 (2011). This is a state-of-the-art review of the development of antiviral compounds, written by one of the pioneers in the field.

    Article  CAS  PubMed  Google Scholar 

  4. Holy, A. Antiviral acyclic nucleoside phosphonates structure activity studies. Antiviral Res. 71, 248–253 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. De Clercq, E. & Holy, A. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nature Rev. Drug Discov. 4, 928–940 (2005).

    Article  CAS  Google Scholar 

  6. Cano-Soldado, P. & Pastor-Anglada, M. Transporters that translocate nucleosides and structural similar drugs: structural requirements for substrate recognition. Med. Res. Rev. 32, 428–457 (2011).

    Article  PubMed  CAS  Google Scholar 

  7. Minuesa, G. et al. Drug uptake transporters in antiretroviral therapy. Pharmacol. Ther. 132, 268–279 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Roizman, B. & Knipe, D. M. in Fundamental Virology (eds Knipe, D. M. & Howley, P. M.) 1123–1184 (Lippincott William and Wilkins, 2001).

    Google Scholar 

  9. Andrei, G. et al. In vitro-selected drug-resistant varicella-zoster virus mutants in the thymidine kinase and DNA polymerase genes yield novel phenotype-genotype associations and highlight differences between antiherpesvirus drugs. J. Virol. 86, 2641–2652 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McGuigan, C. et al. Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus. J. Antimicrob. Chemother. 60, 1316–1330 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Jordheim, L. P. & Dumontet, C. Review of recent studies on resistance to cytotoxic deoxynucleoside analogues. Biochim. Biophys. Acta 1776, 138–159 (2007).

    CAS  PubMed  Google Scholar 

  13. Jordheim, L. P., Seve, P., Tredan, O. & Dumontet, C. The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. Lancet Oncol. 12, 693–702 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Marechal, R. et al. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology 143, 664–674 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Spratlin, J. et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin. Cancer Res. 10, 6956–6961 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Yue, L. et al. A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. Pharmacogenetics 13, 29–38 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Ciccolini, J., Mercier, C., Dahan, L. & André, N. Integrating pharmacogenetics into gemcitabine dosing — time for a change? Nature Rev. Clin. Oncol. 8, 439–444 (2011). This article assesses cytidine deaminase activity in patients receiving gemcitabine.

    Article  CAS  Google Scholar 

  18. Ciccolini, J. et al. Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies. J. Clin. Oncol. 28, 160–165 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Rosell, R. et al. Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin. Cancer Res. 10, 4215s–4219s (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Marechal, R. et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin. Cancer Res. 15, 2913–2919 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Geutjes, E. J., Tian, S., Roepman, P. & Bernards, R. Deoxycytidine kinase is overexpressed in poor outcome breast cancer and determines responsiveness to nucleoside analogs. Breast Cancer Res. Treat. 131, 809–818 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Marechal, R. et al. Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. Cancer 116, 5200–5206 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Galmarini, C. M. et al. Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia. Blood 98, 1922–1926 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Suzuki, K. et al. Clinical significance of high-Km 5′-nucleotidase (cN-II) mRNA expression in high-risk myelodysplastic syndrome. Leuk. Res. 31, 1343–1349 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Robins, M. J. et al. Improved syntheses of 5′-S-(2-aminoethyl)-6-N-(4-nitrobenzyl)-5′-thioadenosine (SAENTA), analogues, and fluorescent probe conjugates: analysis of cell-surface human equilibrative nucleoside transporter 1 (hENT1) levels for prediction of the antitumor efficacy of gemcitabine. J. Med. Chem. 53, 6040–6053 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Tang, M. W., Liu, T. F. & Shafer, R. W. The HIVdb system for HIV-1 genotypic resistance interpretation. Intervirology 55, 98–101 (2012).

    Article  PubMed  Google Scholar 

  27. Tang, M. W. & Shafer, R. W. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs 72, e1–e25 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zoulim, F. & Locarnini, S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 137, 1593–1608 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Bushman, F. D. et al. Massively parallel pyrosequencing in HIV research. AIDS 22, 1411–1415 (2008).

    Article  PubMed  Google Scholar 

  30. Newman, R. M. et al. Whole genome pyrosequencing of rare hepatitis C virus genotypes enhances subtype classification and identification of naturally occurring drug resistance variants. J Infect. Dis. 6 Nov 2012 (doi:10.1093/infdis/jis679).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Solmone, M. et al. Use of massively parallel ultradeep pyrosequencing to characterize the genetic diversity of hepatitis B virus in drug-resistant and drug-naive patients and to detect minor variants in reverse transcriptase and hepatitis B S antigen. J. Virol. 83, 1718–1726 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Ford, L. T. & Berg, J. D. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J. Clin. Pathol. 63, 288–295 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Adam de Beaumais, T. & Jacqz-Aigrain, E. Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur. J. Clin. Pharmacol. 68, 1233–1242 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Eichelbaum, M., Ingelman-Sundberg, M. & Evans, W. E. Pharmacogenomics and individualized drug therapy. Annu. Rev. Med. 57, 119–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Kantarjian, H. et al. Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study. Lancet Oncol. 13, 1096–1104 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Krett, N. L. et al. 8-amino-adenosine is a potential therapeutic agent for multiple myeloma. Mol. Cancer Ther. 3, 1411–1420 (2004).

    CAS  PubMed  Google Scholar 

  37. Gandhi, V. et al. 8-chloro-cAMP and 8-chloro-adenosine act by the same mechanism in multiple myeloma cells. Cancer Res. 61, 5474–5479 (2001). This study shows the multiple and uncommon mechanisms of action of 8-chloro-adenosine; this compound acts as an analogue of ATP and is not incorporated into DNA.

    CAS  PubMed  Google Scholar 

  38. Frey, J. A. & Gandhi, V. 8-amino-adenosine inhibits multiple mechanisms of transcription. Mol. Cancer Ther. 9, 236–245 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stellrecht, C. M., Ayres, M., Arya, R. & Gandhi, V. A unique RNA-directed nucleoside analog is cytotoxic to breast cancer cells and depletes cyclin E levels. Breast Cancer Res. Treat. 121, 355–364 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Stellrecht, C. M., Phillip, C. J., Cervantes-Gomez, F. & Gandhi, V. Multiple myeloma cell killing by depletion of the MET receptor tyrosine kinase. Cancer Res. 67, 9913–9920 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Yang, S. Y. et al. Inhibition of topoisomerase II by 8-chloro-adenosine triphosphate induces DNA double-stranded breaks in 8-chloro-adenosine-exposed human myelocytic leukemia K562 cells. Biochem. Pharmacol. 77, 433–443 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Gu, Y. Y. et al. 8-chloro-adenosine inhibits growth at least partly by interfering with actin polymerization in cultured human lung cancer cells. Biochem. Pharmacol. 72, 541–550 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Choi, W. J. et al. Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity. J. Med. Chem. 55, 4521–4525 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Peters, G. J. et al. Metabolism and mechanism of action of fluorocyclopentenylcytosine (RX-3117). in: 103rd Annual Meeting of the American Association for Cancer Research (Chicago, Illinois, USA; 2012).

    Google Scholar 

  45. Tiwari, K. N. et al. Synthesis of 4′-thio-beta-D-arabinofuranosylcytosine (4′-thio-ara-C) and comparison of its anticancer activity with that of ara-C. Nucleosides Nucleotides Nucleic Acids 19, 329–340 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, C. P. et al. A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies. Clin. Cancer Res. 12, 2841–2848 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Waud, W. R., Gilbert, K. S., Shepherd, R. V., Montgomery, J. A. & Secrist, J. A. Preclinical antitumor activity of 4′-thio-beta-D-arabinofuranosylcytosine (4′-thio-ara-C). Cancer Chemother. Pharmacol. 51, 422–426 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Someya, H., Waud, W. R. & Parker, W. B. Long intracellular retention of 4′-thio-arabinofuranosylcytosine 5′-triphosphate as a critical factor for the anti-solid tumor activity of 4′-thio-arabinofuranosylcytosine. Cancer Chemother. Pharmacol. 57, 772–780 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Stuyver, L. J. et al. Inhibition of the subgenomic hepatitis C virus replicon in huh-7 cells by 2′-deoxy-2′-fluorocytidine. Antimicrob. Agents Chemother. 48, 651–654 (2004). This paper reports the importance of the fluoro group at the 2′ position of cytidine for improved antiviral activity and specificity, as viral polymerases seem to be more tolerant towards the incorporation of such a compound.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Clark, J. L. et al. Design, synthesis, and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J. Med. Chem. 48, 5504–5508 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Pierra, C. et al. Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine. J. Med. Chem. 49, 6614–6620 (2006). This study highlights the discovery of valopicitabine, which was the first nucleoside analogue to be evaluated for the treatment of patients with HCV infection.

    Article  CAS  PubMed  Google Scholar 

  52. O'Brien, C. et al. Randomized trial of valopicitabine (NM283), alone or with peg-interferon, versus retreatment with peg-interferon plus ribavirin (pegifn/RBV) in hepatitis C patients with previous non-response to pegIFN/RBV: first interim results. Hepatology 42, 234A (2005).

    Google Scholar 

  53. Pockros, P. J. et al. JUMP-C: a randomized trial of mericitabine plus peginterferon alfa-2a/ribavirin for 24 weeks in treatment-naive HCV genotype 1/4 patients. Hepatology 28 Jan 2013 (doi:10.1002/hep.26275).

    Article  CAS  PubMed  Google Scholar 

  54. Wedemeyer, H. et al. PROPEL: a randomized trial of mericitabine plus peginterferon alfa-2a/ribavirin therapy in treatment-naive HCV genotype 1/4 patients. Hepatology 24 Jan 2013 (doi:10.1002/hep.26274).

    Article  CAS  PubMed  Google Scholar 

  55. Le Pogam, S. et al. RG7128 alone or in combination with pegylated interferon-alpha2a and ribavirin prevents hepatitis C virus (HCV) replication and selection of resistant variants in HCV-infected patients. J. Infect. Dis. 202, 1510–1519 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Reddy, R. et al. Antiviral activity, pharmacokinetics, safety and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy. Hepatology 46, 862A–863A (2007).

    Google Scholar 

  57. Chu, T. W. et al. Effect of IL28B genotype on early viral kinetics during interferon-free treatment of patients with chronic hepatitis C. Gastroenterology 142, 790–795 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Gane, E. J. et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 376, 1467–1475 (2010). This is one of the first reports to describe the combinational use of a nucleoside analogue in an interferon-free regimen in patients with HCV infection.

    Article  CAS  PubMed  Google Scholar 

  59. DeJesus, E. et al. Elvucitabine versus lamivudine with tenofovir and efavirenz in ART-naïve HIV-1-infected patients: 96-week final results. in: 17th Conference on Retroviruses and Opportunistic Infections [online], (San Francisco, California, USA; 2010).

    Google Scholar 

  60. Bethell, R. C., Lie, Y. S. & Parkin, N. T. In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs. Antivir. Chem. Chemother. 16, 295–302 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Gu, Z. et al. In vitro antiretroviral activity and in vitro toxicity profile of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus infection. Antimicrob. Agents Chemother. 50, 625–631 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cahn, P. & Wainberg, M. A. Resistance profile of the new nucleoside reverse transcriptase inhibitor apricitabine. J. Antimicrob. Chemother. 65, 213–217 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Nitanda, T. et al. Anti-human immunodeficiency virus type 1 activity and resistance profile of 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine in vitro. Antimicrob. Agents Chemother. 49, 3355–3360 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, X., Tanaka, H., Baba, M. & Cheng, Y. C. Retention of metabolites of 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine, a novel anti-human immunodeficiency virus type 1 thymidine analog, in cells. Antimicrob. Agents Chemother. 53, 3317–3324 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. De Clercq, E. Highlights in antiviral drug research: antivirals at the horizon. Med. Res. Rev. 2 May 2012 (10.1002/med.21256).

  66. Price, N. B. & Prichard, M. N. Progress in the development of new therapies for herpesvirus infections. Curr. Opin. Virol. 1, 548–554 (2011). This review presents new therapies for herpesvirus infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kern, E. R. et al. Oral activity of a methylenecyclopropane analog, cyclopropavir, in animal models for cytomegalovirus infections. Antimicrob. Agents Chemother. 48, 4745–4753 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chou, S. & Bowlin, T. L. Cytomegalovirus UL97 mutations affecting cyclopropavir and ganciclovir susceptibility. Antimicrob. Agents Chemother. 55, 382–384 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Secrist, J. A., Tiwari, K. N., Riordan, J. M. & Montgomery, J. A. Synthesis and biological activity of 2′-deoxy-4′-thio pyrimidine nucleosides. J. Med. Chem. 34, 2361–2366 (1991).

    Article  CAS  PubMed  Google Scholar 

  70. Kumar, S. et al. DNA containing 4′-thio-2′-deoxycytidine inhibits methylation by HhaI methyltransferase. Nucleic Acids Res. 25, 2773–2783 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Thottassery, J. V., Tiwari, K., Westbrook, L., Secrist, J. A. & Parker, W. B. Novel 2′-deoxycytidine analogs as DNA demethylation agents. Abstract 2537 in: 102nd Annual Meeting of the American Association for Cancer Research (Orlando, Florida, USA; 2011).

    Google Scholar 

  72. Marquez, V. E. et al. Zebularine: a unique molecule for an epigenetically based strategy in cancer chemotherapy. Ann. NY Acad. Sci. 1058, 246–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Cheng, J. C. et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J. Natl Cancer Inst. 95, 399–409 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Wagner, C. R., Iyer, V. V. & McIntee, E. J. Pronucleotides: toward the in vivo delivery of antiviral and anticancer nucleotides. Med. Res. Rev. 20, 417–451 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Rosowsky, A., Kim, S. H., Ross, J. & Wick, M. M. Lipophilic 5′-(alkyl phosphate) esters of 1-beta-D-arabinofuranosylcytosine and its N4-acyl and 2,2′-anhydro-3′-O-acyl derivatives as potential prodrugs. J. Med. Chem. 25, 171–178 (1982).

    Article  CAS  PubMed  Google Scholar 

  76. Jordheim, L. P. et al. Characterization of a gemcitabine-resistant murine leukemic cell line: reversion of in vitro resistance by a mononucleotide prodrug. Clin. Cancer Res. 10, 5614–5621 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Hantz, O. et al. The SATE pronucleotide approach applied to acyclovir: part II. Effects of bis(SATE)phosphotriester derivatives of acyclovir on duck hepatitis B virus replication in vitro and in vivo. Antiviral Res. 40, 179–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Meier, C. & Balzarini, J. Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules. Antiviral Res. 71, 282–292 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Bontemps, F. et al. Study of the efficacy of a pronucleotide of 2-chloro-2′-deoxyadenosine in deoxycytidine kinase-deficient lymphoma cells. Nucleosides Nucleotides Nucleic Acids 25, 997–1000 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Erion, M. D. et al. Design, synthesis, and characterization of a series of cytochrome P(450) 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver. J. Am. Chem. Soc. 126, 5154–5163 (2004). This study reports the feasibility of the 'HepDirect' approach with several nucleosides.

    Article  CAS  PubMed  Google Scholar 

  81. Erion, M. D. et al. Liver-targeted drug delivery using HepDirect prodrugs. J. Pharmacol. Exp. Ther. 312, 554–560 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Reddy, K. R. et al. Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B. J. Med. Chem. 51, 666–676 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. McGuigan, C. et al. A phosphoramidate ProTide (NUC-1031) and acquired and intrinsic resistance to gemcitabine. J. Clin. Oncol. Abstr. S29, 13540 (2011).

    Article  Google Scholar 

  84. Vail, D. M. et al. Assessment of GS-9219 in a pet dog model of non-Hodgkin's lymphoma. Clin. Cancer Res. 15, 3503–3510 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Ben-Kasus, T., Ben-Zvi, Z., Marquez, V. E., Kelley, J. A. & Agbaria, R. Metabolic activation of zebularine, a novel DNA methylation inhibitor, in human bladder carcinoma cells. Biochem. Pharmacol. 70, 121–133 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Yoo, C. B. et al. Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2′-deoxyzebularine. J. Med. Chem. 51, 7593–7601 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lam, A. M. et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob. Agents Chemother. 56, 3359–3368 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lalezari, J. et al. Once daily PSI-7977 plus PEGIFN/RBV in a phase 2b trial: rapid virologic suppression in treatment-naive patients with HCV GT2/GT3. J. Hepatol. 54, S28 (2011).

    Article  Google Scholar 

  89. Gane, E. J. et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N. Engl. J. Med. 368, 34–44 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Sulkowski, M. S. et al. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV genotype 1, 2, or 3. in: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (Boston, Massachusetts, USA; 2012).

    Google Scholar 

  91. Sulkowski, M. et al. Potent viral suppression with all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (NS5B inhibitor), +/− ribavirin, in treatment-naive patients with chronic HCV GT1, 2, or 3. J. Hepatol. 56, S560 (2012). This was one of the first reports to describe the combinational use of a nucleoside analogue in an interferon-free regimen in patients with HCV infection.

    Google Scholar 

  92. Cretton-Scott, E. et al. In vitro antiviral activity and pharmacology of IDX184, a novel and potent inhibitor of HCV replication. J. Hepatol. 48, S220 (2008).

    Article  Google Scholar 

  93. Lalezari, J. et al. Antiviral activity, safety and pharmacokinetics of IDX184, a liver-targeted nucleotide HCV polymerase inhibitor, in patients with chronic hepatitis C. Hepatology 50, 11A–12A (2009).

    Google Scholar 

  94. McCarville, J. F. et al. No resistance to IDX184 was detected in 3-day and 14-day clinical studies of IDX184 in genotype 1-infected HCV subjects. J. Hepatol. 54, S488–S489 (2011).

    Article  Google Scholar 

  95. Chapman, H. et al. Practical synthesis, separation, and stereochemical assignment of the PMPA pro-drug GS-7340. Nucleosides Nucleotides Nucleic Acids 20, 621–628 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Babusis, D., Phan, T. K., Lee, W. A., Watkins, W. J. & Ray, A. S. Mechanism for effective lymphoid cell and tissue loading following oral administration of nucleotide prodrug GS-7340. Mol Pharm (2012).

  97. Lee, W. A. et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob. Agents Chemother. 49, 1898–1906 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ruane, P. et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir 300 mg in a 10-day monotherapy study of HIV-1+ patients. Abstract 103 in: 19th Conference on Retroviruses and Opporunistic Infections [online], (Seattle, Washington, USA; 2012).

    Google Scholar 

  99. Uckun, F. M., Pendergrass, S., Venkatachalam, T. K., Qazi, S. & Richman, D. Stampidine is a potent inhibitor of Zidovudine- and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical human immunodeficiency virus type 1 isolates with thymidine analog mutations. Antimicrob. Agents Chemother. 46, 3613–3616 (2002). This paper highlights the discovery of a compound that is active on multidrug-resistant HIV strains.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cahn, P. et al. Preclinical and first-in-human Phase I clinical evaluation of stampidine, a potent anti-HIV pharmaceutical drug candidate. J. AIDS Clin. Res. 3, 138 (2012).

    Article  Google Scholar 

  101. Uckun, F. M., Cahn, P., Qazi, S. & D'Cruz, O. Stampidine as a promising antiretroviral drug candidate for pre-exposure prophylaxis against sexually transmitted HIV/AIDS. Expert Opin. Investig. Drugs 21, 489–500 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Ryu, E. K. et al. Phospholipid-nucleoside conjugates. 3. Syntheses and preliminary biological evaluation of 1-beta-D-arabinofuranosylcytosine 5′-monophosphate-l-1,2-dipalmitin and selected 1-beta-D-arabinofuranosylcytosine 5-diphosphate-l-1,2-diacylglycerols. J. Med. Chem. 25, 1322–1329 (1982).

    Article  CAS  PubMed  Google Scholar 

  103. Aoshima, M., Tsukagoshi, S., Sakurai, Y., Oh-ishi, J. I. & Ishida, T. N4-Behenoyl-1-beta-D-arabinofuranosylcytosine as a potential new antitumor agent. Cancer Res. 37, 2481–2486 (1977).

    CAS  PubMed  Google Scholar 

  104. Breistol, K. et al. Antitumor activity of P-4055 (elaidic acid-cytarabine) compared to cytarabine in metastatic and s.c. human tumor xenograft models. Cancer Res. 59, 2944–2949 (1999).

    CAS  PubMed  Google Scholar 

  105. Adema, A. D. et al. Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126. Invest. New Drugs 30, 1908–1916 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Galmarini, C. M., Myhren, F. & Sandvold, M. L. CP-4055 and CP-4126 are active in ara-C and gemcitabine-resistant lymphoma cell lines. Br. J. Haematol. 144, 273–275 (2009).

    Article  PubMed  Google Scholar 

  107. Immordino, M. L. et al. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. J. Control Release 100, 331–346 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Brusa, P., Immordino, M. L., Rocco, F. & Cattel, L. Antitumor activity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. Anticancer Res. 27, 195–199 (2007).

    CAS  PubMed  Google Scholar 

  109. Chung, W. G., Sandoval, M. A., Sloat, B. R., Lansakara, P. D. & Cui, Z. Stearoyl gemcitabine nanoparticles overcome resistance related to the over-expression of ribonucleotide reductase subunit M1. J. Control Release 157, 132–140 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Bergman, A. M. et al. Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinofuranosylcytosine in leukemia and solid tumor cell lines. Biochem. Pharmacol. 67, 503–511 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Bergman, A. M. et al. Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models. Invest. New Drugs 29, 456–466 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Damaraju, V. L. et al. Role of human nucleoside transporters in the uptake and cytotoxicity of azacitidine and decitabine. Nucleosides Nucleotides Nucleic Acids 31, 236–255 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Garcia-Manteiga, J., Molina-Arcas, M., Casado, F. J., Mazo, A. & Pastor-Anglada, M. Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2′,2′-difluorodeoxycytidine-induced cytotoxicity. Clin. Cancer Res. 9, 5000–5008 (2003).

    CAS  PubMed  Google Scholar 

  114. Couvreur, P. et al. Discovery of new hexagonal supramolecular nanostructures formed by squalenoylation of an anticancer nucleoside analogue. Small 4, 247–253 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Reddy, L. H. et al. Anticancer efficacy of squalenoyl gemcitabine nanomedicine on 60 human tumor cell panel and on experimental tumor. Mol. Pharm. 6, 1526–1535 (2009). This study validates the in vitro feasibility of the squalenoylation approach.

    Article  CAS  PubMed  Google Scholar 

  116. Rejiba, S. et al. Squalenoyl gemcitabine nanomedicine overcomes the low efficacy of gemcitabine therapy in pancreatic cancer. Nanomedicine 7, 841–849 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Sarpietro, M. G. et al. Synthesis of n-squalenoyl cytarabine and evaluation of its affinity with phospholipid bilayers and monolayers. Int. J. Pharm. 406, 69–77 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Cosco, D. et al. Self-assembled squalenoyl-cytarabine nanostructures as a potent nanomedicine for treatment of leukemic diseases. Int. J. Nanomed. 7, 2535–2546 (2012).

    CAS  Google Scholar 

  119. Maksimenko, A. et al. Polyisoprenoyl gemcitabine conjugates self assemble as nanoparticles, useful for cancer therapy. Cancer Lett. (2012).

  120. Kiew, L. V., Cheong, S. K., Sidik, K. & Chung, L. Y. Improved plasma stability and sustained release profile of gemcitabine via polypeptide conjugation. Int. J. Pharm. 391, 212–220 (2012).

    Article  CAS  Google Scholar 

  121. Pasut, G. et al. Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid. J. Control Release 127, 239–248 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. El-Mabhouh, A. A. & Mercer, J. R. 188Re-labelled gemcitabine/bisphosphonate (Gem/BP): a multi-functional, bone-specific agent as a potential treatment for bone metastases. Eur. J. Nucl. Med. Mol. Imag. 35, 1240–1248 (2008).

    Article  CAS  Google Scholar 

  123. El-Mabhouh, A. A. et al. A conjugate of gemcitabine with bisphosphonate (Gem/BP) shows potential as a targeted bone-specific therapeutic agent in an animal model of human breast cancer bone metastases. Oncol. Res. 19, 287–295 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Guo, P. et al. Targeted delivery of a peripheral benzodiazepine receptor ligand-gemcitabine conjugate to brain tumors in a xenograft model. Cancer Chemother. Pharmacol. 48, 169–176 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Strasser, S. et al. 5-FdUrd-araC heterodinucleoside re-establishes sensitivity in 5-FdUrd- and AraC-resistant MCF-7 breast cancer cells overexpressing ErbB2. Differ. 74, 488–498 (2006).

    Article  CAS  Google Scholar 

  126. Lanier, E. R. et al. Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV. Antimicrob. Agents Chemother. 54, 2901–2909 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. McGuigan, C. et al. Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base. J. Med. Chem. 42, 4479–4484 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Pentikis, H. S. et al. Pharmacokinetics and safety of FV-100, a novel oral anti-herpes zoster nucleoside analogue, administered in single and multiple doses to healthy young adult and elderly adult volunteers. Antimicrob. Agents Chemother. 55, 2847–2854 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Brueckner, B. et al. Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Mol. Cancer Ther. 9, 1256–1264 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Veltkamp, S. A. et al. Oral administration of gemcitabine in patients with refractory tumors: a clinical and pharmacologic study. Clin. Cancer Res. 14, 3477–3486 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Bender, D. M. et al. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J. Med. Chem. 52, 6958–6961 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Pratt, S. E. et al. Human carboxylesterase 2 hydrolyzes the prodrug of gemcitabine (LY2334737) and confers prodrug sensitivity to cancer cells. Clin. Cancer Res. 19, 1159–1168 (2013).

    Article  CAS  PubMed  Google Scholar 

  133. Koolen, S. L. et al. Phase I study of oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients with advanced solid tumors. Clin. Cancer Res. 17, 6071–6082 (2011). This is the first report of the clinical use of an orally active gemcitabine conjugate.

    Article  CAS  PubMed  Google Scholar 

  134. Hao, W. H. et al. In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation. Cancer Chemother. Pharmacol. 71, 379–388 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Maloisel, F. et al. Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase. Leukemia 16, 573–580 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Mollee, P. et al. Interferon-alpha-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia. Ann. Oncol. 15, 1810–1815 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Horikoshi, A., Takei, K., Hosokawa, Y. & Sawada, S. The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients. Int. J. Hematol. 87, 118–125 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Gokbuget, N. et al. Liposomal cytarabine is effective and tolerable in the treatment of central nervous system relapse of acute lymphoblastic leukemia and very aggressive lymphoma. Haematologica 96, 238–244 (2011).

    Article  PubMed  CAS  Google Scholar 

  139. Calvagno, M. G. et al. Effects of lipid composition and preparation conditions on physical-chemical properties, technological parameters and in vitro biological activity of gemcitabine-loaded liposomes. Curr. Drug Deliv. 4, 89–101 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. Arias, J. L., Reddy, L. H. & Couvreur, P. Superior preclinical efficacy of gemcitabine developed as chitosan nanoparticulate system. Biomacromolecules 12, 97–104 (2011).

    Article  CAS  PubMed  Google Scholar 

  141. Celia, C., Cosco, D., Paolino, D. & Fresta, M. Gemcitabine-loaded innovative nanocarriers versus GEMZAR: biodistribution, pharmacokinetic features and in vivo antitumor activity. Expert Opin. Drug Deliv. 8, 1609–1629 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Feldman, E. J. et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J. Clin. Oncol. 29, 979–985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhao, X., Wu, J., Muthusamy, N., Byrd, J. C. & Lee, R. J. Liposomal coencapsulated fludarabine and mitoxantrone for lymphoproliferative disorder treatment. J. Pharm. Sci. 97, 1508–1518 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Rose, W. C., Crosswell, A. R., Bronson, J. J. & Martin, J. C. In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues. J. Natl Cancer Inst. 82, 510–512 (1990).

    Article  CAS  PubMed  Google Scholar 

  145. Holy, A. et al. Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro. Antiviral Res. 13, 295–311 (1990).

    Article  CAS  PubMed  Google Scholar 

  146. Tsai, C. Y. et al. Targeting DNA repair in chronic lymphocytic leukemia cells with a novel acyclic nucleotide analogue, GS-9219. Clin. Cancer Res. 15, 3760–3769 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Suzuki, N., Nakagawa, F., Nukatsuka, M. & Fukushima, M. Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks. Exp. Ther. Med. 2, 393–397 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Temmink, O. H. et al. Trifluorothymidine resistance is associated with decreased thymidine kinase and equilibrative nucleoside transporter expression or increased secretory phospholipase A2. Mol. Cancer Ther. 9, 1047–1057 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Emura, T., Murakami, Y., Nakagawa, F., Fukushima, M. & Kitazato, K. A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int. J. Mol. Med. 13, 545–549 (2004).

    CAS  PubMed  Google Scholar 

  150. Yoshino, T. et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 13, 993–1001 (2012).

    Article  CAS  PubMed  Google Scholar 

  151. Clouser, C. L. et al. Anti-HIV-1 activity of resveratrol derivatives and synergistic inhibition of HIV-1 by the combination of resveratrol and decitabine. Bioorg. Med. Chem. Lett. 22, 6642–6646 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Clouser, C. L. et al. Analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. PLoS ONE 6, e15840 (2011). This study reports on the antiviral activity of the cytotoxic nucleoside analogue gemcitabine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Elwell, L. P. et al. Antibacterial activity and mechanism of action of 3′-azido-3′-deoxythymidine (BW A509U). Antimicrob. Agents Chemother. 31, 274–280 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lewin, C. S., Allen, R. A. & Amyes, S. G. Mechanisms of zidovudine resistance in bacteria. J. Med. Microbiol. 33, 235–238 (1990).

    Article  CAS  PubMed  Google Scholar 

  155. Doleans-Jordheim, A. et al. Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains. Eur. J. Clin. Microbiol. Infect. Dis. 30, 1249–1256 (2011).

    Article  CAS  PubMed  Google Scholar 

  156. Jordheim, L. P. et al. Gemcitabine is active against clinical multiresistant Staphylococcus aureus strains and is synergistic with gentamicin. Int. J. Antimicrob. Agents 39, 444–447 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Groves, A. M., Win, T., Haim, S. B. & Ell, P. J. Non-[18F]FDG PET in clinical oncology. Lancet Oncol. 8, 822–830 (2007).

    Article  PubMed  Google Scholar 

  158. Giovannoni, G. et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 362, 416–426 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Tatlisumak, T. et al. Delayed treatment with an adenosine kinase inhibitor, GP683, attenuates infarct size in rats with temporary middle cerebral artery occlusion. Stroke 29, 1952–1958 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Sharma, N. K., Mahadevan, N. & Balakumar, P. Adenosine transport blockade restores attenuated cardioprotective effects of adenosine preconditioning in the isolated diabetic rat heart: potential crosstalk with opioid receptors. Cardiovasc. Toxicol. 13, 22–32 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Richman, D. D. HIV chemotherapy. Nature 410, 995–1001 (2001).

    Article  CAS  PubMed  Google Scholar 

  162. Leyssen, P., De Clercq, E. & Neyts, J. Molecular strategies to inhibit the replication of RNA viruses. Antiviral Res. 78, 9–25 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Broder, C. C. Henipavirus outbreaks to antivirals: the current status of potential therapeutics. Curr. Opin. Virol. 2, 176–187 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Chevaliez, S., Brillet, R., Lazaro, E., Hezode, C. & Pawlotsky, J. M. Analysis of ribavirin mutagenicity in human hepatitis C virus infection. J. Virol. 81, 7732–7741 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Vignuzzi, M., Stone, J. K. & Andino, R. Ribavirin and lethal mutagenesis of poliovirus: molecular mechanisms, resistance and biological implications. Virus Res. 107, 173–181 (2005).

    Article  CAS  PubMed  Google Scholar 

  166. Ewald, B., Sampath, D. & Plunkett, W. Nucleoside analogs: molecular mechanisms signaling cell death. Oncogene 27, 6522–6537 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. McGinn, C. J., Shewach, D. S. & Lawrence, T. S. Radiosensitizing nucleosides. J. Natl Cancer Inst. 88, 1193–1203 (1996).

    Article  CAS  PubMed  Google Scholar 

  168. Kantarjian, H. et al. Phase I clinical and pharmacokinetic study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. J. Clin. Oncol. 28, 285–291 (2010). This study shows the clinical safety of the new oral nucleoside analogue sapacitabine.

    Article  CAS  PubMed  Google Scholar 

  169. Gilbert, J., Carducci, M. A., Baker, S. D., Dees, E. C. & Donehower, R. A. Phase I study of the oral antimetabolite, CS-682, administered once daily 5 days per week in patients with refractory solid tumor malignancies. Invest. New Drugs 24, 499–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Delaunoit, T. et al. A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors. Invest. New Drugs 24, 327–333 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Radhakrishnan, S. K. & Gartel, A. L. A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits antiangiogenic activity. Cancer Res. 66, 3264–3270 (2006).

    Article  CAS  PubMed  Google Scholar 

  172. Nekhai, S. et al. A novel anticancer agent ARC antagonizes HIV-1 and HCV. Oncogene 26, 3899–3903 (2007).

    Article  CAS  PubMed  Google Scholar 

  173. Bhat, U. G. & Gartel, A. L. Nucleoside analog ARC targets Mcl-1 to induce apoptosis in leukemia cells. Leukemia 24, 851–855 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Le Guerhier, F. et al. Antiviral activity of beta-l-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine in woodchucks chronically infected with woodchuck hepatitis virus. Antimicrob. Agents Chemother. 45, 1065–1077 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lin, T. S. et al. Design and synthesis of 2′,3′-dideoxy-2′,3′-didehydro-beta-l-cytidine (beta-l-d4C) and 2′,3′-dideoxy 2′,3′-didehydro-beta-l-5-fluorocytidine (beta-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. 39, 1757–1759 (1996).

    Article  CAS  PubMed  Google Scholar 

  176. Le Guerhier, F. et al. Characterization of the antiviral effect of 2′,3′-dideoxy-2′, 3′-didehydro-beta-l-5-fluorocytidine in the duck hepatitis B virus infection model. Antimicrob. Agents Chemother. 44, 111–122 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Cahn, P. et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. Aids 20, 1261–1268 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Wainberg, M. A., Cahn, P., Bethell, R. C., Sawyer, J. & Cox, S. Apricitabine: a novel deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of nucleoside-resistant HIV infection. Antivir. Chem. Chemother. 18, 61–70 (2007).

    Article  CAS  PubMed  Google Scholar 

  179. Gouy, M. H. et al. Special feature of mixed phosphotriester derivatives of cytarabine. Bioorg. Med. Chem. 17, 6340–6347 (2009).

    Article  CAS  PubMed  Google Scholar 

  180. Tobias, S. C. & Borch, R. F. Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug. Mol. Pharm. 1, 112–116 (2004).

    Article  CAS  PubMed  Google Scholar 

  181. Rodriguez-Torres, M. et al. Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naive patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial. J Hepatol 58, 663–668 (2012).

    Article  PubMed  CAS  Google Scholar 

  182. Lawitz, E. et al. High rapid virologic response (RVR) with PSI-7977 qd plus PEG-IFN/RBV in a 28-day phase 2a trial. Hepatology 52, 706A (2010). This is a description of the antiviral activity of sofosbuvir, which is probably the first 'pure chain terminator' nucleotide analogue to be used against HCV.

    Google Scholar 

  183. Vernachio, J. H. et al. INX-08189, a phosphoramidate prodrug of 6-O-methyl-2′-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob. Agents Chemother. 55, 1843–1851 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. O'Brien, S. et al. Elacytarabine has single-agent activity in patients with advanced acute myeloid leukaemia. Br. J. Haematol. 158, 581–588 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Giles, F. et al. Elacytarabine, a novel 5′-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia. Leuk. Res. 36, e71–e73 (2012). This is a report on the clinical activity of the elaidic acid derivative of cytarabine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Bildstein, L. et al. Transmembrane diffusion of gemcitabine by a nanoparticulate squalenoyl prodrug: an original drug delivery pathway. J. Control Release 147, 163–170 (2010).

    Article  CAS  PubMed  Google Scholar 

  187. Chuang, J. C. et al. S110, a 5-aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol. Cancer Ther. 9, 1443–1450 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Yoo, C. B. et al. Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 67, 6400–6408 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Painter, G. R. et al. Evaluation of hexadecyloxypropyl-9-R−[2-(phosphonomethoxy)propyl]-adenine, CMX157, as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections. Antimicrob. Agents Chemother. 51, 3505–3509 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Painter, W. et al. First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob. Agents Chemother. 56, 2726–2734 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the support of the Association pour la Recherche sur le Cancer (ARC) and the Ligue contre le Cancer. L.P.J. acknowledges the Olav Raagholt and Gerd Meidel Raagholt Foundation for Research (Olav Raagholt og Gerd Meidel Raagholts stiftelse for medisinsk forskning).

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Authors and Affiliations

  1. Anticancer Antibody Team, Institut National de la Santé et de la Recherche Médicale (INSERM) U1052, Centre national de la recherche scientifique UMR 5286, Cancer Research Center of Lyon, Faculté Rockefeller, 8 Ave Rockefeller, Lyon, 69008, France

    Lars Petter Jordheim & Charles Dumontet

  2. Hematology Laboratory, Hospices Civils de Lyon, Lyon, F-69000, France

    Lars Petter Jordheim, Fabien Zoulim & Charles Dumontet

  3. Pathogenesis of hepatitis B and C infection team, Institut National de la Santé et de la Recherche Médicale (INSERM) U1052, Centre national de la recherche scientifique UMR 5286, Cancer Research Center of Lyon, 151 cours Albert Thomas, Lyon Cedex 03, 69424, France

    David Durantel & Fabien Zoulim

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Correspondence to Lars Petter Jordheim, David Durantel, Fabien Zoulim or Charles Dumontet.

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Competing interests

F.Z. has received consulting/speaking fees from Gilead, Bristol-Myers Squibb and Janssen Cilag.

F.Z. and D.D. have received research grants from Roche.

C.D. and L.P.J. have received research grants from Clavis Pharma.

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Supplementary information

Supplementary information S1 (table)

Currently approved nucleos(t)ide analogues and indications (PDF 113 kb)

Supplementary information S2 (table)

Main enzymatic activities targeted by nucleos(t)ide analogues for different chronic viruses (PDF 118 kb)

Supplementary information S3 (table)

Mutations in different viral polymerases conferring resistance to nucleos(t)ide analogues (PDF 138 kb)

Supplementary information S4 (table)

Associations between genetic variants and response to nucleoside analogue therapy in cancer patients (PDF 147 kb)

Glossary

Ribonucleotide reductase

A complex intracellular enzyme that converts ribonucleoside diphosphates into deoxyribonucleoside diphosphates, and is targeted by anticancer agents such as gemcitabine.

Nucleobase

A nitrogen-containing heterocyclic compound that can be grouped into purines (adenine and guanine) and pyrimidines (cytosine, thymine and uracil).

Dose adaptation

Determination of the dose that should be administered to a patient based on predicted or observed toxicity.

Demethylating agents

Compounds that modify the methylation status of regulatory sequences in DNA, thereby modifying the levels of expression of the corresponding gene.

Nucleoside transporters

Membrane pumps that allow the uptake and/or the efflux of nucleosides by cells.

Chain elongation

The increase in length of DNA or RNA strands during replication or transcription.

Phenotypic assays

Assays in which biological function or cell response is measured as an index of drug action.

Pronucleotides

Phosphorylated nucleosides in which the phosphate is linked to a protective group to increase diffusion of the nucleoside across the cell membrane.

Nucleophilic attack

A chemical reaction in which a negatively charged entity forms a bond with a positively charged atom.

Prodrugs

Compounds that are administered as inactive pharmacological entities that are then metabolized in vivo into an active compound.

Sustained viral response

The absence of detectable virus in the blood for up to 6 months after treatment.

First-pass hepatic metabolism

The uptake and metabolism of an orally administered drug by enzymes in the liver, which reduces the concentration of the drug in the systemic circulation.

Phase 0 trial

A first-in-human clinical trial that is carried out to determine the pharmacodynamic and pharmacokinetic properties of a drug.

Drug repositioning

A strategy in which drugs that were initially developed in a given indication are subsequently applied to a novel indication.

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Jordheim, L., Durantel, D., Zoulim, F. et al. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 12, 447–464 (2013). https://doi.org/10.1038/nrd4010

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