Antiproliferative activity, cell-cycle dysregulation, and cellular differentiation: salicyl- and catechol-derived acyclic 5-fluorouracil O,N-acetals against breast cancer cells.
Herein we report the preparation and biological activity of three compounds with the general formula 1-[2-(5-substituted-2-hydroxybenzyloxy)-1-methoxyethyl]-5-fluorouracil. 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-methoxybut-3-enyl]-5-fluorouracil [(Z)-11] 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)-11: IC(50)=9.40+/-0.64 microM. Differentiated breast cancer cells generate fat deposits in the cytoplasm. MCF-7 cells treated with (Z)-11 underwent an increase in lipid content relative to control cells after three 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.
Marchal
Juan A
JA
Instituto de Biopatología y Medicina Regenerativa (IBIMER), Departamento de Anatomía y Embriología Humana, Facultad de Medicina, Avenida de Madrid s/n, 18071 Granada, Spain.
Rodríguez-Serrano
Fernando
F
Caba
Octavio
O
Aránega
Antonia
A
Gallo
Miguel A
MA
Espinosa
Antonio
A
Campos
Joaquín M
JM
D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil