Synthesis and Properties of Lipophilic Derivatives of 5-
Fluorouracil

A. V. Semakov, A. A. Blinkov, G. P. Gaenko, A. G. Vostrova, and J. G. Molotkovsky¹

Shemyakin—Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences,
ul. Miklukho-Maklaya 16/10, Moscow, 117997 Russia

Received December 12, 2012; in final form, December 24, 2012

Abstract—A series of N¹-acyl derivatives of 5-fluorouracil (5-FU) bearing the residues of palmitic, p-myris-
toylaminobenzoic, p-oleoylaminobenzoic, and adamantane-1-carboxylic acids have been synthesized. The rel-
ative hydrolysis rates for the derivatives under physiological conditions (pH 7.2 and 37C) have been deter-
mined, and it has been shown that the resistance of these compounds to hydrolysis increases as the steric acces-
sibility of the amide group at residue N¹ 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 M) 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.

Keywords: 5-fluorouracil, N-acyl derivatives, cytostatic activity, lipophilic predrugs, liposomes, fluorescent
analogue

DOI: 10.1134/S1068162013030138

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