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Accessible Unlicensed Requires Authentication Published by De Gruyter March 27, 2017

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

Nuno M. Xavier ORCID logo, Rita Gonçalves-Pereira ORCID logo, Radek Jorda ORCID logo, Eva Řezníčková ORCID logo, Vladimír Kryštof ORCID logo and M. Conceição Oliveira ORCID logo


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.


‘Fundação para a Ciência e Tecnologia’ (FCT) is acknowledged for funding through the FCT Investigator Program (IF/01488/2013), the exploratory project IF/01488/2013/CP1159/CT0006 and the strategic project UID/MULTI/00612/2013. RJ, EŘ and VK gratefully acknowledge support from the Ministry of Education, Youth and Sports of the Czech Republic (the National Program of Sustainability I – Grant LO1204).


[1] C. M. Galmarini, F. Popowycz, B. Joseph. Curr. Med. Chem.15, 1072 (2008).Search in Google Scholar

[2] L. P. Jordheim, D. Durantel, F. Zoulim, C. Dumontet. Nat. Rev. Drug. Discov.12, 447 (2013).Search in Google Scholar

[3] C. Simons, Q. Wu, T. T. Htar. Curr. Top. Med. Chem.5, 1191 (2005).Search in Google Scholar

[4] S. Rachakonda, L. Cartee. Curr. Med. Chem.11, 775 (2004)Search in Google Scholar

[5] M. Winn, R. J. M. Goss, K.-i. Kimura, T. D. H. Bugg. Nat. Prod. Rep.27, 279 (2010)Search in Google Scholar

[6] M. Serpi, V. Ferrari, F. Pertusati. J. Med. Chem.59, 10343 (2016).Search in Google Scholar

[7] N. M. Xavier, S. Schwarz, P. D. Vaz, R. Csuk, A. P. Rauter. Eur. J. Org. Chem.2014, 2770 (2014).Search in Google Scholar

[8] S. Schwarz, R. Csuk, A. P. Rauter. Org. Biomol. Chem.12, 2446 (2014).Search in Google Scholar

[9] D. Batista, S. Schwarz, A. Loesche, R.Csuk, P. J. Costa, M. C. Oliveira, N. M. Xavier. Pure Appl. Chem.88, 363 (2016).Search in Google Scholar

[10] A. E. Tomkinson, T. R. L. Howes, N. E. Wiest. Transl. Cancer Res.2, 1219 (2013)Search in Google Scholar

[11] T. Helleday, E. Petermann, C. Lundin, B. Hodgson, R. A. Sharma. Nat. Rev. Cancer8, 193 (2008).Search in Google Scholar

[12] K. Ghoshal, S. Bai. Drugs Today43, 395 (2007).Search in Google Scholar

[13] D. Subramaniam, R. Thombre, A. Dhar, S. Anant. Front. Oncol.4, 80 (2014).Search in Google Scholar

[14] L. Tedaldia, G. K. Wagner. Med. Chem. Commun.5, 1106 (2014).Search in Google Scholar

[15] S. S. Pinho, C. A. Reis. Nat. Rev. Cancer15, 540 (2015).Search in Google Scholar

[16] A. M. Fajardo, G. A. Piazza, H. N. Tinsley. Cancers6, 436 (2014).Search in Google Scholar

[17] K. Yan, L. N. Gao, Y. L. Cui, Y. Zhang, X. Zhou. Mol. Med. Rep.13, 3715 (2016).Search in Google Scholar

[18] A. Caretta, C. Mucignat-Caretta. Cancers3, 913 (2011).Search in Google Scholar

[19] K. Bian, F. Murad. Adv Exp Med Biol.814, 5 (2014).Search in Google Scholar

[20] P. Liu, H. Cheng, T. M. Roberts, J. J. Zhao. Nat. Rev. Drug Discov.8, 627 (2009).Search in Google Scholar

[21] P. Wu, Y. Z. Hu. Curr. Med. Chem.17, 4326 (2010).Search in Google Scholar

[22] J. Polivka Jr., F. Janku. Pharmacol. Ther.142, 164 (2014).Search in Google Scholar

[23] S. Lapenna, A. Giordano. Nat. Rev. Drug Discov.8, 547 (2009).Search in Google Scholar

[24] M. Aarts, S. Linardopoulos, N. C. Turner. Curr. Opin. Pharmacol.13, 529 (2013).Search in Google Scholar

[25] T. A. Chohan, H. Qian, Y. Pan, J.-Z. Chen. Curr. Med. Chem.22, 237 (2015).Search in Google Scholar

[26] U. Asghar, A. K. Witkiewicz, N. C. Turner, E. S. Knudsen. Nat. Rev. Drug Discov.14, 130 (2015).Search in Google Scholar

[27] U. Pradere, E. C. Garnier-Amblard, S. J. Coats, F. Amblard, R. F. Schinazi. Chem. Rev.114, 9154 (2014).Search in Google Scholar

[28] C. M. Galmarini, J. R. Mackey, C. Dumontet. Leukemia15, 875 (2001).Search in Google Scholar

[29] V. L. Damaraju, S. Damaraju, J. D. Young, S. A. Baldwin, J. Mackey, M. B. Sawyer, C. E. Cass. Oncogene22, 7524 (2003).Search in Google Scholar

[30] J. Zhang, F. Visser, K. M. King, S. A. Baldwin, J. D. Young, C. E. Cass. Cancer Metastasis Rev.26, 85 (2007).Search in Google Scholar

[31] H. K. Bhatia, H. Singh, N. Grewal, N. K. Natt. J. Pharmacol. Pharmacother.5, 278 (2014).Search in Google Scholar

[32] L. Tang, H. Ward, S. Kattakuzhy, E. Wilson, S. Kottilil. Expert Rev. Gastroenterol. Hepatol.10, 21, (2016).Search in Google Scholar

[33] G.M. Keating, Drugs74, 1127 (2014).Search in Google Scholar

[34] S. C. Tobias, R. F. Borch. Mol. Pharm.1, 112 (2004).Search in Google Scholar

[35] D. Katalenić, V. Škarić. J. Chem. Soc., Perkin Trans. 1 1065 (1992).Search in Google Scholar

[36] D. Katalenić, V. Škarić, B. Klaić. Tetrahedron Lett.35, 2743 (1994).Search in Google Scholar

[37] D. Williamson, M. J. Cann, D. R. W. Hodgson. Chem. Commun. 5096 (2007).Search in Google Scholar

[38] D. Williamson, D. R. W. Hodgson. Org. Biomol. Chem.6, 1056 (2008).Search in Google Scholar

[39] R. L. Letsinger, J. S. Wilkes, L. B. Dumas. J. Am. Chem. Soc.94, 292 (1972).Search in Google Scholar

[40] R. L. Letsinger, B. Hapke, G. R. Petersen, L. B. Dumas. Nucleic Acids Res.3, 1053 (1976).Search in Google Scholar

[41] R. L. Letsinger, J. S. Wilkes. Biochemistry15, 2810 (1976).Search in Google Scholar

[42] J. L. Wolfe, T. Kawate, A. Belenky, V. Stanton Jr. Nucl. Acids Res.30, 3739 (2002).Search in Google Scholar

[43] W. Kotkowiak, A. Pasternak, R. Kierzek. PLoS One11, e0148282 (2016).Search in Google Scholar

[44] J. P. Neenan, W. Rohde. J. Med. Chem.16, 580 (1973).Search in Google Scholar

[45] M. S. Chen, D. C. Ward, W. H. Prusoff. J. Biol Chem.251, 4833 (1976).Search in Google Scholar

[46] T.-S. Lin, J. P. Neenan, Y.-C. Cheng, W. H. Prusoff. J. Med. Chem. 19, 495 (1976).Search in Google Scholar

[47] S. K. Roberts, G. Cooksley, G. J. Dore, R. Robson, D. Shaw, H. Berns, G. Hill, K. Klumpp, I. Najera, C. Washington. Hepatology48, 398 (2008).Search in Google Scholar

[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).Search in Google Scholar

[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).Search in Google Scholar

[50] T. Pathak. Chem. Rev.102, 1623 (2002).Search in Google Scholar

[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).Search in Google Scholar

[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).Search in Google Scholar

[53] Z. Györgideák, J. Thiem. Adv. Carbohydr. Chem. Biochem.60, 103 (2006).Search in Google Scholar

[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).Search in Google Scholar

[55] C. E. McKenna, M. T. Higa, N. H. Cheung, M.-C. McKenna. Tetrahedron Lett.18, 155 (1977).Search in Google Scholar

[56] A. J. Gutierrez, E. J. Prisbe, J. C. Rohloff. Nucleos. Nucleot. Nucleic Acids20, 1299 (2001).Search in Google Scholar

[57] B. C. Challis, J. A. Challis, J. N. Iley. J. Chem. Soc., Perkin Trans. 2 813 (1978).Search in Google Scholar

[58] I. Wilkening, G. del Signore, C. P. R. Hackenberger. Chem. Commun. 2932 (2008).Search in Google Scholar

[59] J. Wang, J. Li, D. Tuttle, J. Y. Takemoto, C.-W. T. Chang. Org. Lett.4, 3997 (2002).Search in Google Scholar

[60] R. K. Harris, E. D. Becker, S. M. Cabral de Menezes, R. Goodfellow, P. Granger. Pure Appl. Chem.73, 1795 (2001).Search in Google Scholar

[61] B. K. Singh, A. K. Yadav, B. Kumar, A. Gaikwad, S. K. Sinha, V. Chaturvedic, R. P. Tripathi. Carbohydr. Res.343, 1153 (2008).Search in Google Scholar

[62] S. G. Hansen, H. H. Jensen. Synlett20, 3275 (2009).Search in Google Scholar

Published Online: 2017-3-27
Published in Print: 2017-8-28

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