Antitumoural properties of benzannelated seven-membered 5-fluorouracil derivatives and related open analogues. Molecular markers for apoptosis and cell cycle dysregulation.
Attention is increasingly being focussed on the cell cycle and apoptosis as potential targets for therapeutic intervention in cancer. We 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 14-membered aminal structures and acyclic compounds. All the cyclic aminals provoked a G0/G1-phase cell cycle arrest, whereas Ftorafur, a known prodrug of 5-FU, and 1-[2-(2-hydroxymethyl-4-nitrophenoxy)-1-methoxyethyl]-5-fluorouracil (11) 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, but improved clinical responses may be obtained by identifying therapies that are particularly effective in activating apoptosis. 1-(2,3-Dihydrobenzoxepin-2-yl)-5-fluorouracil (5) may be particularly useful in stimulating apoptosis in breast cancer.
Espinosa
Antonio
A
Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja, s/n, 18071 Granada, Spain. aespinos@ugr.es
Marchal
Juan A
JA
Aránega
A
A
Gallo
Miguel A
MA
Aiello
Stefania
S
Campos
Joaquín
J
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001555:Benzene Derivatives / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D015195:Drug Design; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D016193:G1 Phase; D019073:HT29 Cells; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D005472:Fluorouracil