Abstract
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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Abbreviations
- ATA:
-
antitumor agent
- 5-FU and L-FU:
-
5-fluorouracil and its lipophilic derivative
- DIPEA:
-
diisopropylethylamine
- ePC:
-
egg phosphatidylcholine
- HBL:
-
human breast lymphoma
- PAB:
-
p-aminobenzoyl
References
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.
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.
Chen, Z.X. and Breitman, T.R., Cancer Res., 1994, vol. 54, pp. 3494–3499.
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.
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.
Giller, S.A., Zhuk, R.A., and Lidak, M.Yu., Dokl. Akad. Nauk SSSR, 1967, vol. 176, pp. 332–225.
Malet-Martino, M.P., Jolimaitre, P., and Martino, R., Curr. Med. Chem, Anti-Cancer Agents, 2002, vol. 2, pp. 267–310.
Pan, X., Wang, C., Wang, F., Li, P., Hu, Z., Shan, Y., and Zhang, J., Curr. Med. Chem., 2011, vol. 18, pp. 4538–4556.
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.
Elorza, B., Elorza, M.A., Frutos, G., and Chantres, J.R., Biochim. Biophys. Acta, 1993, vol. 1153, pp. 135–142.
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.
Murakami, T., Biotechnol. J., 2012, vol. 7, pp. 762–767.
Kumar, P., Gulbake, A., and Jain, S.K., Crit. Rev. Ther. Drug Carrier Syst., 2012, vol. 29, pp. 355–419.
Straubinger, R.M., Arnold, R.D., Zhou, R., Mazurchuk, R., and Slack, J.E., Anticancer Res., 2004, vol. 24, no. 2.
Yu, B., Tai, H.C., Xue, W., Lee, L.J., and Lee, R.J., Mol. Membr. Biol., 2010, vol. 27, pp. 286–298.
Basile, L., Pignatello, R., and Passirani, C., Curr. Drug Deliv., 2012, vol. 9, pp. 255–268.
Tada, M., US Patent No. 3971784, 1976.
Ishida, T., Nishimura, D., Sugawara, T., and Ooka, T., US Patent No. 4088646, 1978.
Robins, M.J. and Hatfield, P.W., Can. J. Chem., 1982, vol. 60, pp. 547–553.
Jolimaitre, P., Malet-Martino, M., and Martino, R., Int. J. Pharm., 2003, vol. 259, pp. 181–192.
Yu, B.T., Sun, X., and Zhang, Z.R., Arch. Pharm. Res., 2003, vol. 26, pp. 1096–1101.
Sun, W., Zhang, N., Li, A., Zou, W., and Xu, W., Int. J. Pharm., 2008, vol. 353, pp. 243–250.
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.
Nishimoto, S., Hatta, H., Ueshima, H., and Kagiya, T., J. Med. Chem., 1992, vol. 35, pp. 2711–2712.
Grechishnikova, I.V., Mikhalev, I.I., and Molotkovsky, J.G., Bioorg. Khim., 1995, vol. 21, pp. 70–76.
Hermetter, A. and Oskolkova, O., US Patent No. 7772402, 2010.
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.
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.
DeVries, V.G., Largis, E.E., Miner, T.G., Shepherd, R.G., and Upelacis, J., J. Med. Chem., 1983, vol. 26, pp. 1411–1423.
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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). https://doi.org/10.1134/S1068162013030138
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DOI: https://doi.org/10.1134/S1068162013030138