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Synthesis and properties of lipophilic derivatives of 5-fluorouracil

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

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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). https://doi.org/10.1134/S1068162013030138

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  • DOI: https://doi.org/10.1134/S1068162013030138

Keywords

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