New Medium Oxacyclic O,N-Acetals and Related Open Analogues: Biological Activities

Author(s): Joaquin Campos, Estrella Saniger, Juan A. Marchal, Stefania Aiello, Ines Suarez, Houria Boulaiz, Antonia Aranega, Miguel A. Gallo, Antonio Espinosa.

Journal Name: Current Medicinal Chemistry

Volume 12 , Issue 12 , 2005

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Abstract:

Attention is increasingly being focussed on the cell cycle and apoptosis as potential targets for therapeutic intervention in cancer. Taking 1-[(2-oxepanyl)]-5-fluorouracil previously prepared by us, we committed ourselves to increase the lipophilicity of this upper cyclohomologue of Ftorafur and prepared a series of bioisosteric benzannelated seven-membered 5-FU O,N-acetals to test them against the MCF-7 human breast cancer cell line. Benzo-fused seven-membered O,O-acetals or their acyclic analogues led to the expected 5-FU O,N-acetals (or aminals), in addition to six- and to 14- membered aminal structures and acyclic compounds. All the cyclic aminals provoked a Go/G1-phase cell cycle arrest, whereas Ftorafur, a known prodrug of 5-FU, and 1-[2-(2-hydroxymethyl-4-nitrophenoxy)-1-methoxyethyl]-5-fluorouracil (51) induced an S-phase cell cycle arrest. Although breast cancer is most often treated with conventional cytotoxic agents it has proved difficult to induce apoptosis in breast cancer cells and, consequently, improved clinical responses may be obtained by identifying therapies that are particularly effective in activating apoptosis. 1-(2,3- Dihydrobenzoxepin-2-yl)-5-fluorouracil (26) may be particularly useful in stimulating apoptosis in breast cancer. This compound is more potent as an apoptotic inductor than paclitaxel (Taxol®). Finally, a fact that is worth emphasizing is that the cyclic and acyclic 5-FU O,N-acetals induce neither toxicity nor death in mice after one months treatment when administered intravenously twice a week, with a 50 mg/kg dose each time. Taken together, the experimental findings provide evidence of specific anti-tumour activity of these new substances and warrant further evaluation in in vivo models of breast cancer to future clinical applications.

Keywords: anti-tumour drugs, breast cancer, cell cycle, programmed cell death, 1-[3-(hydroxymethyl)-1,4-dioxepan-5-yl]pyrimidines, benzodioxepins, neighbouring group participation, lipophilicity

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Article Details

VOLUME: 12
ISSUE: 12
Year: 2005
Page: [1423 - 1438]
Pages: 16
DOI: 10.2174/0929867054020927
Price: $58

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