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Acyclonucleosides, salicyl- and catechol-derived acyclic 5-fluorouracil O,N-acetals: Antiproliferative activities, apoptosis and cellular differentiation
Juan A. Marchal,a Antonia Aránega,a MiguelA. Gallo,b Antonio Espinosa,b Joaquín M. Camposb,[*]
aInstituto de Biopatología y Medicina Regenerativa (IBIMER). Departamento de Anatomía y Embriología Humana. Facultad de Medicina, Avenida de Madrid s/n, 18071 Granada (Spain)
bDepartamento de Química Farmacéutica y Orgánica. Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada (Spain)
Novel prodrug derivatives of 5-fluorouracil (5-FU) possessing a broader spectrum of antitumour activity and fewer toxic side effects than 5-FU have been sought diligently in a number of laboratories. The emergence of acyclovir as an excellent antiviral agent stimulated the synthesis of a wide variety of acyclic nucleosides modified either in the base or the acyclic part. To our knowledge no attempt has been made to use seven-membered cycloacetals to synthesize acyclonucleosides. Our aim was to fill this gap and in this review we report the synthesis and antitumour activity of acyclonucleoside 5-FU derivatives through the SnCl4-catalyzed opening of alkoxy-1,4-diheteroepanes by the 2,4-bis(trimethylsilyloxy)-5-fluorouracil generated in situ in dry acetonitrile. The acyclonucleosides reported here are especially interesting due to the following two reasons: (a) the presence of the hydroxyl group in the side chain that could therefore be phosphorylated; and (b) the fact that they constitute a new class of antitumour agents, since 5-FU is bound to a cytostatic aldehyde such as acrolein or some of its homologues and, accordingly, two active substances are combined in one drug.
The goal of cancer chemotherapy with classical drugs – the destruction of the tumour cells – is often complicated by significant toxicity. Differentiation therapy is a new approach to cancer treatment which assumes that neoplastic transformation reveals the inability of a cell population to couple proliferation and differentiation signals. Induced differentiation modulates the cell programme by transforming malignant cells into mature cells with no proliferative potential. Studies in rhabdomyosarcoma tumours, the most frequent soft tissue malignancy in paediatric patients, have shown that the malignant phenotype can be repressed to some degree, and that the tumour cellscan be induced to re-enter the differentiation process. Our data demonstrate that (RS)-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. On the other hand, (RS)-1-{[3-(3-chloro-2-hydroxypropoxy)-1-methoxy]propyl}-5-fluorouracil (QF-3602)showed in rhabdomyosarcoma cells a low toxicity and time-dependent growth inhibition. Scanning and transmission electron microscopy and immunocytochemical analyses showed that QF-3602 induced the appearance of myofilaments along the myotube-like giant RD cells, an increase of fibronectin and a decrease in vimentin expression. In contrast, only minor changes were observed with 5-FU. Moreover, polymerase chain reaction (PCR) analyses showed that QF-3602 did not induce overexpression of the mdr 1 gene, a resistant mechanism that frequently appears in classical cytotoxic therapy in these tumours.
From a designing point of view, we fused a benzene ring to the side chain in order to increase the lipophilicity and anticancer activity of our molecules. Herein we will 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)-1] 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)-1 with an IC50 = 9.40 ± 0.64 M. Differentiated breast cancer cells generate fat deposits within the cytoplasm. The MCF-7 cells treated with (Z)-1 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.
Although in vivo studies will be necessary, the findings of the present study suggest that (Z)-1 may be useful as an agent for differentiation therapy against the MCF-7 human breast cancer cell line and might have tumour selective activity. 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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