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: Acyclic O, N-acetals, acyclonucleosides, breast cancer, cellular differentiation, 5-fluorouracil
Current Medicinal Chemistry
Title: Acyclonucleosides, Modified Seco-Nucleosides, and Salicyl- or Catechol- Derived Acyclic 5-Fluorouracil O,N-Acetals: Antiproliferative Activities, Cellular Differentiation and Apoptosis
Volume: 16 Issue: 9
Author(s): Juan A. Marchal, Maria C. Nunez, Antonia Aranega, Miguel A. Gallo, Antonio Espinosa and Joaquin M. Campos
Affiliation:
Keywords: Acyclic O, N-acetals, acyclonucleosides, breast cancer, cellular differentiation, 5-fluorouracil
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.
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Marchal A. Juan, Nunez C. Maria, Aranega Antonia, Gallo A. Miguel, Espinosa Antonio and Campos M. Joaquin, Acyclonucleosides, Modified Seco-Nucleosides, and Salicyl- or Catechol- Derived Acyclic 5-Fluorouracil O,N-Acetals: Antiproliferative Activities, Cellular Differentiation and Apoptosis, Current Medicinal Chemistry 2009; 16 (9) . https://dx.doi.org/10.2174/092986709787581824
DOI https://dx.doi.org/10.2174/092986709787581824 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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