Synthesis and evaluation of new 5-fluorouracil antitumor cell differentiating derivatives

Abstract

Abstract-Three new antitumour drugs containing two 5-fluorouracil moieties at both ends of the structure and a two amide bond linker were synthesized. Appropriated bis-acetal were reacted with two equivalents of 5-FU to afford the desired compounds. These drugs were evaluated for their ability to induce myogenic maturation in vitro on human rhabdomyosarcoma cells in an experimental model. Compounds 5 and 6 induced morphological and phenotypical differentiation in rhabdomyosarcoma cells at 4.5 and 3.5 mM, respectively. These new cell differentiating agents could be used as an alternative to selective destruction of undifferentiated cells. A potential role of the differentiation therapy as an alternative approach to the treatment of rhabdomyosarcomas is suggested. #

5-Fluorouracil Derivatives Induce Differentiation Mediated by Tubulin and HLA Class I Modulation

“…Compounds 4, 5 and 6 significantly proved to increase two-fold the desmin expression in comparison with that of parental cells. However, the percentage of vimentin-positive cells decreased significantly after 6 days of treatment [28].…”

“…Methyl 3-methoxy-3-(5-fluorouracil-1-yl)propanoate (6) was prepared from 3,3-methyl dimethoxypropanoate under our standard conditions [28]. Compounds 4 and 5 induced morphological and phenotypical differentiation in the RMS cell line at 4.5 and 3.5 M, respectively.…”

Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

“…Recently, the concept of mutual prodrugs in which two different antineoplastic agents are coupled directly or by means of a spacer has become well accepted [8][9][10][11][12][13][14][15][16][17]. This technique can be used to overcome many problems including poor solubility or absorption, patient acceptability, drug instability and toxicity, and especially drug resistance [11].…”

5-Fluorouracil derivatives: a patent review (2012 – 2014)

“…The technique to couple two different prodrugs has tried to overcome 5-FU-related complications like poor drug solubility and/or absorption, toxicity and drug resistance [11]. The combination of 5-FU with antineoplastic DNA binders, which alter the DNA and favor 5-FU to reach its target, have been evaluated and resulted in an increased efficiency of both 5-FU and the DNA binders [11][12][13]. To avoid another of the inherent complications of 5-FU such as its poor tissue specificity, some investigators have directed their attention to find molecules that could help the prodrug to target a specific tissue [14].…”