title: Antitumoural properties of benzannelated seven-membered 5-fluorouracil derivatives and related open analogues. Molecular markers for apoptosis and cell cycle dysregulation.
abstract: 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.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja, s/n, 18071 Granada, Spain. aespinos@ugr.es
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
authors.forename: Juan A
authors.initials: JA
authors.lastname: Marchal
authors.forename: A
authors.initials: A
authors.lastname: Aránega
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Stefania
authors.initials: S
authors.lastname: Aiello
authors.forename: Joaquín
authors.initials: J
authors.lastname: Campos
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D005472:Fluorouracil