title: Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs.
abstract: Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances the toxicity of DNA-damaging agents towards p53-defective cancer cells. The relationship between structure and G2 checkpoint inhibition was determined for 56 caffeine analogs. Replacement of the methyl group at position 3 or 7 resulted in loss of activity, while replacement at position 1 by ethyl or propyl increased activity slightly. 8-Substituted caffeines retained activity, but were relatively insoluble. The structure-activity profile did not resemble those for other known pharmacological activities of caffeine. The active analogs also potentiated the killing of p53-defective cells by ionizing radiation, but none was as effective as caffeine.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.forename: L Y
authors.initials: LY
authors.lastname: Lim
authors.forename: J W
authors.initials: JW
authors.lastname: Daly
authors.forename: A H
authors.initials: AH
authors.lastname: Li
authors.forename: K A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: M
authors.initials: M
authors.lastname: Roberge
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D002110:Caffeine / Q000031:analogs & derivatives* / Q000737:chemistry; D003037:Cobalt Radioisotopes; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D003037:Cobalt Radioisotopes; D016159:Tumor Suppressor Protein p53; D002110:Caffeine