title: Synthesis of a prodrug designed to release multiple inhibitors of the epidermal growth factor receptor tyrosine kinase and an alkylating agent: a novel tumor targeting concept.
abstract: The synthesis of a novel acetoxymethyltriazene designed to be a prodrug of multiple inhibitors of the epidermal growth factor receptor (EGFR) and a methyldiazonium species is described. Studies with each of the expected metabolites demonstrated significant EGFR tyrosine kinase inhibitory activities and the released methyldiazonium was trapped with p-nitrobenzylpyridine. Their ability to damage genomic DNA in whole cells was demonstrated by using the single cell microelectrophoresis (comet) assay. The results suggest that this approach may well represent a novel drug combination strategy involving single molecules masking multiple bioactive agents.
authors.affiliation: Department of Medicine, McGill University Health Center/Royal Victoria Hospital, Montreal, H3A 1A1 Quebec, Canada.
authors.forename: Ranjita
authors.initials: R
authors.lastname: Banerjee
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Rachid
authors.forename: James
authors.initials: J
authors.lastname: McNamee
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D020552:Comet Assay; D004249:DNA Damage; D003979:Diazonium Compounds / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014226:Triazenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003979:Diazonium Compounds; D004791:Enzyme Inhibitors; D011355:Prodrugs; D014226:Triazenes; D066246:ErbB Receptors