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 G(o)/G(1)-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 month's 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.