Acyclonucleosides, Modified Seco-Nucleosides, and Salicyl- or Catechol- Derived Acyclic 5-Fluorouracil O,N-Acetals: Antiproliferative Activities, Cellular Differentiation and Apoptosis

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Abstract:

The goal of cancer chemotherapy with classical drugs - the destruction of the tumor cells - is often complicated by significant toxicity. As an alternative, induced differentiation modulates the cell programme by transforming malignant cells into mature cells with no proliferative potential. Our data demonstrate that (+/-)-1-{[3-(2-hydroxyethoxy)-1- isopropoxy]propyl}-5-fluorouracil inhibits proliferation, induces myogenic differentiation, increases the expression of proteins specifically present in normally differentiated skeletal muscle cells, and modifies the adhesion capacity of these cells against the rhabdomyosarcoma cell line RD. From a designing point of view, a benzene ring was fused to the side chain in order to increase the lipophilicity and anticancer activity of our molecules. Herein we report the preparation and biological activity of three compounds having the general formula (+/-)-1-[2-(5-substituted-2-hydroxybenzyloxy)-1- methoxyethyl]-5-fluorouracils. A catechol-derived compound such as (+/-)-1-[3-(2-hydroxyphenoxy)-1-methoxypropyl]- 5-fluorouracil and two salicyl-derived compounds such as (+/-)-(Z)-1-[4-(2-hydroxyphenyl)-1-methoxy-but-3-enyl]-5- fluorouracil [(Z)-43] and its dihydrogenated derivative (+/-)-1-[4-(2-hydroxyphenyl)-1-methoxybutyl]-5-fluorouracil were prepared to complete the set of six O,N-acetals. The most active compound against the MCF-7 breast cancer cell line was (+/-)-(Z)-43 with an IC50 = 9.40 ± 0.64 μM. Differentiated breast cancer cells generate fat deposits within the cytoplasm. The MCF-7 cells treated with (+/-)-(Z)-43 caused an increase in the lipid content over control cells after 3 days of treatment. Our results suggest that there may be significant potential advantages in the use of this new differentiating agent for the treatment of breast cancer.

Keywords: 5-fluorouracil; Acyclic O; N-acetals; acyclonucleosides; breast cancer; cellular differentiation

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986709787581824

Affiliations: Departamento de Quimica Farmaceutica y Organica. Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain.

Publication date: March 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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