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Synthesis and properties of lipophilic derivatives of 5-fluorouracil


A series of N 1-acyl derivatives of 5-fluorouracil (5-FU) bearing the residues of palmitic, p-myristoylaminobenzoic, p-oleoylaminobenzoic, and adamantane-1-carboxylic acids have been synthesized. The relative hydrolysis rates for the derivatives under physiological conditions (pH 7.2 and 37°C) have been determined, and it has been shown that the resistance of these compounds to hydrolysis increases as the steric accessibility of the amide group at residue N 1 of 5-FU decreases. The derivatives easily incorporate into the lipid bilayer; their liposomal preparations show a marked cytostatic activity on human breast lymphoma cells (LD50 ∼1 μM) and are of interest as potential antitumor preparations. In addition, a fluorescent analogue of the above derivatives, 1-[8-(3-perylenyl)octanoyl]-5-fluorouracil, has been synthesized, which is intended for studying the behavior of 5-FU derivatives in cells and tissues by instrumental methods.

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antitumor agent

5-FU and L-FU:

5-fluorouracil and its lipophilic derivative




egg phosphatidylcholine


human breast lymphoma




  1. Heidelberger, C., Chaudhuri, N.K., Danneberg, P., Mooren, D., Griesbach, L., Duschinsky, R., Schnitzer, R.J., Pleven, E., and Scheiner, J., Nature, 1957, vol. 179, pp. 663–666.

    PubMed  Article  CAS  Google Scholar 

  2. Noordhuis, P., Holwerda, U., Van der Wilt, C.L., Van Groeningen, C.J., Smid, K., Meijer, S., Pinedo, H.M., and Peters, G.J., Ann. Oncol., 2004, vol. 15, pp. 1025–1032.

    PubMed  Article  CAS  Google Scholar 

  3. Chen, Z.X. and Breitman, T.R., Cancer Res., 1994, vol. 54, pp. 3494–3499.

    PubMed  CAS  Google Scholar 

  4. Peters, G.J., Backus, H.H., Freemantle, S., van Triest, B., Codacci-Pisanelli, G., Van der Wilt, C.L., Smid, K., Lunec, J., Calvert, A.H., Marsh, H., McLeod, H.L., Bloemena, E., Meijers, G., Jansen, G., Van Groeningen, C.J., and Pinedo, H.M., Biochim. Biophys. Acta, 2002, vol. 1587, pp. 194–205.

    PubMed  Article  CAS  Google Scholar 

  5. Funaki, N.O., Tanaka, J., Kohmoto, M., Sugiyama, T., Ohshio, G., Nonaka, A., Yotsumoto, F., Takeda, Y., and Imamura, M., Oncol. Rep., 2001, vol. 8, pp. 527–532.

    PubMed  CAS  Google Scholar 

  6. Giller, S.A., Zhuk, R.A., and Lidak, M.Yu., Dokl. Akad. Nauk SSSR, 1967, vol. 176, pp. 332–225.

    PubMed  CAS  Google Scholar 

  7. Malet-Martino, M.P., Jolimaitre, P., and Martino, R., Curr. Med. Chem, Anti-Cancer Agents, 2002, vol. 2, pp. 267–310.

    Article  CAS  Google Scholar 

  8. Pan, X., Wang, C., Wang, F., Li, P., Hu, Z., Shan, Y., and Zhang, J., Curr. Med. Chem., 2011, vol. 18, pp. 4538–4556.

    PubMed  Article  CAS  Google Scholar 

  9. Alvarez, P., Marchal, J.A., Boulaiz, H., Carrillo, E., Velez, C., Rodriguez-Serrano, F., Melguizo, C., Prados, J., Madeddu, R., and Aranega, A., Expert Opin. Ther. Patents, 2012, vol. 22, pp. 107–123.

    Article  CAS  Google Scholar 

  10. Elorza, B., Elorza, M.A., Frutos, G., and Chantres, J.R., Biochim. Biophys. Acta, 1993, vol. 1153, pp. 135–142.

    PubMed  Article  CAS  Google Scholar 

  11. Thomas, A.M., Kapanen, A.I., Hare, J.I., Ramsay, E., Edwards, K., Karlsson, G., and Bally, M.B., J. Control. Release, 2011, vol. 150, pp. 212–219.

    PubMed  Article  CAS  Google Scholar 

  12. Murakami, T., Biotechnol. J., 2012, vol. 7, pp. 762–767.

    PubMed  Article  CAS  Google Scholar 

  13. Kumar, P., Gulbake, A., and Jain, S.K., Crit. Rev. Ther. Drug Carrier Syst., 2012, vol. 29, pp. 355–419.

    PubMed  Article  CAS  Google Scholar 

  14. Straubinger, R.M., Arnold, R.D., Zhou, R., Mazurchuk, R., and Slack, J.E., Anticancer Res., 2004, vol. 24, no. 2.

    Google Scholar 

  15. Yu, B., Tai, H.C., Xue, W., Lee, L.J., and Lee, R.J., Mol. Membr. Biol., 2010, vol. 27, pp. 286–298.

    PubMed  Article  CAS  Google Scholar 

  16. Basile, L., Pignatello, R., and Passirani, C., Curr. Drug Deliv., 2012, vol. 9, pp. 255–268.

    PubMed  Article  CAS  Google Scholar 

  17. Tada, M., US Patent No. 3971784, 1976.

  18. Ishida, T., Nishimura, D., Sugawara, T., and Ooka, T., US Patent No. 4088646, 1978.

  19. Robins, M.J. and Hatfield, P.W., Can. J. Chem., 1982, vol. 60, pp. 547–553.

    Article  CAS  Google Scholar 

  20. Jolimaitre, P., Malet-Martino, M., and Martino, R., Int. J. Pharm., 2003, vol. 259, pp. 181–192.

    PubMed  Article  CAS  Google Scholar 

  21. Yu, B.T., Sun, X., and Zhang, Z.R., Arch. Pharm. Res., 2003, vol. 26, pp. 1096–1101.

    PubMed  Article  CAS  Google Scholar 

  22. Sun, W., Zhang, N., Li, A., Zou, W., and Xu, W., Int. J. Pharm., 2008, vol. 353, pp. 243–250.

    PubMed  Article  CAS  Google Scholar 

  23. Vodovozova, E.L., Moiseeva, E.V., Gaenko, G.P., Bovin, N.V., and Molotkovsky, J.G., Russ.. Bioterapevt. Zh., 2008, vol. 7, no. 2, pp. 24–33.

    CAS  Google Scholar 

  24. Nishimoto, S., Hatta, H., Ueshima, H., and Kagiya, T., J. Med. Chem., 1992, vol. 35, pp. 2711–2712.

    PubMed  Article  CAS  Google Scholar 

  25. Grechishnikova, I.V., Mikhalev, I.I., and Molotkovsky, J.G., Bioorg. Khim., 1995, vol. 21, pp. 70–76.

    CAS  Google Scholar 

  26. Hermetter, A. and Oskolkova, O., US Patent No. 7772402, 2010.

    Google Scholar 

  27. Menezes, D.E.L., Kirchmeier, M.J., Gagne, J.F., Pilarski, L.M., and Allen, T.M., J. Liposome Res., 1999, vol. 9, pp. 199–228.

    Article  Google Scholar 

  28. Vodovozova, E.L., Moiseeva, E.V., Grechko, G.K., Gayenko, G.P., Nifant’ev, N.E., Bovin, N.V., and Molotkovsky, J.G., Eur. J. Cancer, 2000, vol. 36, pp. 942–949.

    PubMed  Article  CAS  Google Scholar 

  29. DeVries, V.G., Largis, E.E., Miner, T.G., Shepherd, R.G., and Upelacis, J., J. Med. Chem., 1983, vol. 26, pp. 1411–1423.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to J. G. Molotkovsky.

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Original Russian Text © A.V. Semakov, A.A. Blinkov, G.P. Gaenko, A.G. Vostrova, J.G. Molotkovsky, 2013, published in Bioorganicheskaya Khimiya, 2013, Vol. 39, No. 3, pp. 338–345.

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Semakov, A.V., Blinkov, A.A., Gaenko, G.P. et al. Synthesis and properties of lipophilic derivatives of 5-fluorouracil. Russ J Bioorg Chem 39, 299–305 (2013).

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  • 5-fluorouracil
  • N-acyl derivatives
  • cytostatic activity
  • lipophilic predrugs
  • liposomes
  • fluorescent analogue