Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs

Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances th e toxicity of DNA-damaging agents towards p53-defective cancer cells. The r elationship between structure and G2 checkpoint inhibition was determined f or 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 p ropyl increased activity slightly. 8-Substituted caffeines retained activit y, but were relatively insoluble. The structure-activity profile did not re semble those for other known pharmacological activities of caffeine. The ac tive analogs also potentiated the killing of p53-defective cells by ionizin g radiation, but none was as effective as caffeine.