Synthesis and antiproliferative evaluation of novel azido nucleosides and their phosphoramidate derivatives

  • 1 Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 2/5º Piso, Campo Grande, 1749-016 Lisboa, Portugal
  • 2 Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
  • 3 Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Nuno M. XavierORCID iD: http://orcid.org/0000-0001-8739-8768, Rita Gonçalves-PereiraORCID iD: http://orcid.org/0000-0002-8501-1627, Radek JordaORCID iD: http://orcid.org/0000-0002-4905-7126
  • Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
  • orcid.org/0000-0002-4905-7126
  • Search for other articles:
  • degruyter.comGoogle Scholar
, Eva ŘezníčkováORCID iD: http://orcid.org/0000-0003-4773-2850
  • Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
  • orcid.org/0000-0003-4773-2850
  • Search for other articles:
  • degruyter.comGoogle Scholar
, Vladimír KryštofORCID iD: http://orcid.org/0000-0001-5838-2118
  • Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic
  • orcid.org/0000-0001-5838-2118
  • Search for other articles:
  • degruyter.comGoogle Scholar
and M. Conceição OliveiraORCID iD: http://orcid.org/0000-0002-3068-4920

Abstract:

New xylofuranosyl and glucopyranosyl nucleoside phosphoramidates were synthesized as potential mimetics of nucleoside 5′-monophosphates. Their access involved N-glycosylation of uracil and 2-acetamido-6-chloropurine with 5′/6′-azido-1,2-di-O-acetyl glycosyl donors and subsequent Staudinger-phosphite reaction of the resulting azido nucleosides. The coupling of the purine derivative with the pyranosyl donor furnished N9- and N7-linked nucleosides in 1:1 ratio, whereas with the furanosyl donor, the N9-nucleoside was the major regioisomer formed. When using uracil, only 5′/6′-azido N1-linked nucleosides were obtained. The purine 5′/6′-azido nucleosides were converted into corresponding phosphoramidates in good yields. The antiproliferative effects of the nucleoside phosphoramidates and those of the azido counterparts on cancer cells were evaluated. While the nucleoside phosphoramidates did not show significant activities, the purine 5′/6′-azido nucleosides displayed potent effects against K562, MCF-7 and BT474 cell lines. The 5′-azidofuranosyl N9 and N7-linked purine nucleosides exhibited highest activity towards the chronic myeloid leukemia cell line (K562) with GI50 values of 13.6 and 9.7 μM, respectively. Among pyranosyl nucleosides, the N7-linked nucleoside was the most active compound with efficacy towards all cell lines assayed and a highest effect on K562 cells (GI50=6.8 μM). Cell cycle analysis of K562 and MCF-7 cells showed that the most active compounds cause G2/M arrest.

  • [1]

    C. M. Galmarini, F. Popowycz, B. Joseph. Curr. Med. Chem. 15, 1072 (2008).

  • [2]

    L. P. Jordheim, D. Durantel, F. Zoulim, C. Dumontet. Nat. Rev. Drug. Discov. 12, 447 (2013).

    • Crossref
    • PubMed
    • Export Citation
  • [3]

    C. Simons, Q. Wu, T. T. Htar. Curr. Top. Med. Chem. 5, 1191 (2005).

  • [4]

    S. Rachakonda, L. Cartee. Curr. Med. Chem. 11, 775 (2004)

  • [5]

    M. Winn, R. J. M. Goss, K.-i. Kimura, T. D. H. Bugg. Nat. Prod. Rep. 27, 279 (2010)

  • [6]

    M. Serpi, V. Ferrari, F. Pertusati. J. Med. Chem. 59, 10343 (2016).

  • [7]

    N. M. Xavier, S. Schwarz, P. D. Vaz, R. Csuk, A. P. Rauter. Eur. J. Org. Chem. 2014, 2770 (2014).

    • Crossref
    • Export Citation
  • [8]

    S. Schwarz, R. Csuk, A. P. Rauter. Org. Biomol. Chem. 12, 2446 (2014).

  • [9]

    D. Batista, S. Schwarz, A. Loesche, R.Csuk, P. J. Costa, M. C. Oliveira, N. M. Xavier. Pure Appl. Chem. 88, 363 (2016).

    • Crossref
    • Export Citation
  • [10]

    A. E. Tomkinson, T. R. L. Howes, N. E. Wiest. Transl. Cancer Res. 2, 1219 (2013)

    • PubMed
    • Export Citation
  • [11]

    T. Helleday, E. Petermann, C. Lundin, B. Hodgson, R. A. Sharma. Nat. Rev. Cancer 8, 193 (2008).

    • Crossref
    • PubMed
    • Export Citation
  • [12]

    K. Ghoshal, S. Bai. Drugs Today 43, 395 (2007).

  • [13]

    D. Subramaniam, R. Thombre, A. Dhar, S. Anant. Front. Oncol. 4, 80 (2014).

    • PubMed
    • Export Citation
  • [14]

    L. Tedaldia, G. K. Wagner. Med. Chem. Commun. 5, 1106 (2014).

  • [15]

    S. S. Pinho, C. A. Reis. Nat. Rev. Cancer 15, 540 (2015).

  • [16]

    A. M. Fajardo, G. A. Piazza, H. N. Tinsley. Cancers 6, 436 (2014).

  • [17]

    K. Yan, L. N. Gao, Y. L. Cui, Y. Zhang, X. Zhou. Mol. Med. Rep. 13, 3715 (2016).

    • Crossref
    • PubMed
    • Export Citation
  • [18]

    A. Caretta, C. Mucignat-Caretta. Cancers 3, 913 (2011).

  • [19]

    K. Bian, F. Murad. Adv Exp Med Biol. 814, 5 (2014).

  • [20]

    P. Liu, H. Cheng, T. M. Roberts, J. J. Zhao. Nat. Rev. Drug Discov. 8, 627 (2009).

  • [21]

    P. Wu, Y. Z. Hu. Curr. Med. Chem. 17, 4326 (2010).

  • [22]

    J. Polivka Jr., F. Janku. Pharmacol. Ther. 142, 164 (2014).

  • [23]

    S. Lapenna, A. Giordano. Nat. Rev. Drug Discov. 8, 547 (2009).

  • [24]

    M. Aarts, S. Linardopoulos, N. C. Turner. Curr. Opin. Pharmacol. 13, 529 (2013).

    • Crossref
    • PubMed
    • Export Citation
  • [25]

    T. A. Chohan, H. Qian, Y. Pan, J.-Z. Chen. Curr. Med. Chem. 22, 237 (2015).

    • PubMed
    • Export Citation
  • [26]

    U. Asghar, A. K. Witkiewicz, N. C. Turner, E. S. Knudsen. Nat. Rev. Drug Discov. 14, 130 (2015).

    • Crossref
    • PubMed
    • Export Citation
  • [27]

    U. Pradere, E. C. Garnier-Amblard, S. J. Coats, F. Amblard, R. F. Schinazi. Chem. Rev. 114, 9154 (2014).

    • Crossref
    • PubMed
    • Export Citation
  • [28]

    C. M. Galmarini, J. R. Mackey, C. Dumontet. Leukemia 15, 875 (2001).

  • [29]

    V. L. Damaraju, S. Damaraju, J. D. Young, S. A. Baldwin, J. Mackey, M. B. Sawyer, C. E. Cass. Oncogene 22, 7524 (2003).

    • Crossref
    • PubMed
    • Export Citation
  • [30]

    J. Zhang, F. Visser, K. M. King, S. A. Baldwin, J. D. Young, C. E. Cass. Cancer Metastasis Rev. 26, 85 (2007).

    • Crossref
    • PubMed
    • Export Citation
  • [31]

    H. K. Bhatia, H. Singh, N. Grewal, N. K. Natt. J. Pharmacol. Pharmacother. 5, 278 (2014).

    • Crossref
    • PubMed
    • Export Citation
  • [32]

    L. Tang, H. Ward, S. Kattakuzhy, E. Wilson, S. Kottilil. Expert Rev. Gastroenterol. Hepatol. 10, 21, (2016).

    • Crossref
    • PubMed
    • Export Citation
  • [33]

    G.M. Keating, Drugs 74, 1127 (2014).

  • [34]

    S. C. Tobias, R. F. Borch. Mol. Pharm. 1, 112 (2004).

  • [35]

    D. Katalenić, V. Škarić. J. Chem. Soc., Perkin Trans. 1 1065 (1992).

  • [36]

    D. Katalenić, V. Škarić, B. Klaić. Tetrahedron Lett. 35, 2743 (1994).

    • Crossref
    • Export Citation
  • [37]

    D. Williamson, M. J. Cann, D. R. W. Hodgson. Chem. Commun. 5096 (2007).

  • [38]

    D. Williamson, D. R. W. Hodgson. Org. Biomol. Chem. 6, 1056 (2008).

  • [39]

    R. L. Letsinger, J. S. Wilkes, L. B. Dumas. J. Am. Chem. Soc. 94, 292 (1972).

  • [40]

    R. L. Letsinger, B. Hapke, G. R. Petersen, L. B. Dumas. Nucleic Acids Res. 3, 1053 (1976).

    • Crossref
    • PubMed
    • Export Citation
  • [41]

    R. L. Letsinger, J. S. Wilkes. Biochemistry 15, 2810 (1976).

  • [42]

    J. L. Wolfe, T. Kawate, A. Belenky, V. Stanton Jr. Nucl. Acids Res. 30, 3739 (2002).

    • Crossref
    • Export Citation
  • [43]

    W. Kotkowiak, A. Pasternak, R. Kierzek. PLoS One 11, e0148282 (2016).

  • [44]

    J. P. Neenan, W. Rohde. J. Med. Chem. 16, 580 (1973).

  • [45]

    M. S. Chen, D. C. Ward, W. H. Prusoff. J. Biol Chem. 251, 4833 (1976).

  • [46]

    T.-S. Lin, J. P. Neenan, Y.-C. Cheng, W. H. Prusoff. J. Med. Chem. 19, 495 (1976).

  • [47]

    S. K. Roberts, G. Cooksley, G. J. Dore, R. Robson, D. Shaw, H. Berns, G. Hill, K. Klumpp, I. Najera, C. Washington. Hepatology 48, 398 (2008).

    • Crossref
    • PubMed
    • Export Citation
  • [48]

    M. R. Mish, A. Cho, T. Kirschberg, J. Xu, C. S. Zonte, M. Fenaux, Y. Park, D. Babusis, J. Y. Feng, A. S. Ray, C. U. Kim. Bioorg. Med. Chem. Lett. 24, 3092 (2014).

    • Crossref
    • PubMed
    • Export Citation
  • [49]

    M. Brandl, X. Wu, M. Holper, L.Hong, Z. Jia, R. Birudaraj, M. Reddy, T. Alfredson, T. Tran, S. Larrabee, X. Hadig, K. Sarma, C. Washington, G. Hill, D. B. Smith. Drug Devel. Ind. Pharm., 34, 683 (2008).

    • Crossref
    • Export Citation
  • [50]

    T. Pathak. Chem. Rev. 102, 1623 (2002).

  • [51]

    J. Pereira, D. Levy, J. L. Ruiz, G. A. Brocardo, K. A. Ferreira, R. O. Costa, R. G. Queiroz, D. A. Maria, A. E. Neto, D. A. Chamone, S. P. Bydlowski. Anti-cancer Agents Med. Chem. 13, 186 (2013).

    • Crossref
    • Export Citation
  • [52]

    Q. Wang, X. Liu, Q. Wang, Y. Zhang, J. Jiang, X. Guo, Q. Fan, L. Zheng, X. Yu, N. Wang, Z. Pan, C. Song, W. Qi, J. Chang. Biochem. Pharmacol. 81, 848 (2011).

    • Crossref
    • PubMed
    • Export Citation
  • [53]

    Z. Györgideák, J. Thiem. Adv. Carbohydr. Chem. Biochem. 60, 103 (2006).

    • Crossref
    • PubMed
    • Export Citation
  • [54]

    Z. J. Witczak. Recent advances in the synthesis of functionalized carbohydrate azides. in Specialist Periodical Reports: Carbohydrate Chemistry, A. P. Rauter, T. Lindhorst, (Eds.), Vol. 36, pp. 176–193, Royal Society of Chemistry, London (2010).

  • [55]

    C. E. McKenna, M. T. Higa, N. H. Cheung, M.-C. McKenna. Tetrahedron Lett. 18, 155 (1977).

    • Crossref
    • Export Citation
  • [56]

    A. J. Gutierrez, E. J. Prisbe, J. C. Rohloff. Nucleos. Nucleot. Nucleic Acids 20, 1299 (2001).

    • Crossref
    • Export Citation
  • [57]

    B. C. Challis, J. A. Challis, J. N. Iley. J. Chem. Soc., Perkin Trans. 2 813 (1978).

  • [58]

    I. Wilkening, G. del Signore, C. P. R. Hackenberger. Chem. Commun. 2932 (2008).

  • [59]

    J. Wang, J. Li, D. Tuttle, J. Y. Takemoto, C.-W. T. Chang. Org. Lett. 4, 3997 (2002).

    • Crossref
    • PubMed
    • Export Citation
  • [60]

    R. K. Harris, E. D. Becker, S. M. Cabral de Menezes, R. Goodfellow, P. Granger. Pure Appl. Chem. 73, 1795 (2001).

    • Crossref
    • Export Citation
  • [61]

    B. K. Singh, A. K. Yadav, B. Kumar, A. Gaikwad, S. K. Sinha, V. Chaturvedic, R. P. Tripathi. Carbohydr. Res. 343, 1153 (2008).

    • Crossref
    • PubMed
    • Export Citation
  • [62]

    S. G. Hansen, H. H. Jensen. Synlett 20, 3275 (2009).

Purchase article
Get instant unlimited access to the article.
$25.00
Log in
Already have access? Please log in.


or
Log in with your institution

Journal + Issues

Pure and Applied Chemistry is the official monthly Journal of the International Union of Pure and Applied Chemistry (IUPAC), with responsibility for publishing works arising from those international scientific events and projects that are sponsored and undertaken by the Union.

Search