title: Design and synthesis of 2-nitroimidazoles with variable alkylating and acylating functionality.
abstract: The synthesis of a small series of 2-nitroimidazoles in which the β-amino alcohol side chain was amidated with a range of alkylating/acylating functionality is described. Synthetic methodologies were developed that generally provided for selective N-acyl versus N,O-bisacyl products. In vitro, target analogs showed minimal radiosensitization activity, with only a few exhibiting a sensitizer enhancement ratio (SER) >2.0 and C(1.6) values comparable to reference agents RB-6145 and RSU-1069. In an assay to determine potential to alkylate biomolecules, representative analogs showed <1% of the alkylating activity of RSU-1069. In vivo, one analog showed an enhancement ratio of 1.6 relative to vehicle control when tested in B6C3F1 mice with an implanted KHT sarcoma. The data reinforce prior findings that there is a correlation between alkylation potential and in vivo activity.
authors.affiliation: Departments of Chemistry and Cancer Research, Pfizer Global Research and Development.
authors.forename: Thomas
authors.initials: T
authors.lastname: Winters
authors.forename: Anthony
authors.initials: A
authors.lastname: Sercel
authors.forename: Carla
authors.initials: C
authors.lastname: Suto
authors.forename: William
authors.initials: W
authors.lastname: Elliott
authors.forename: Wilbur
authors.initials: W
authors.lastname: Leopold
authors.forename: Judith
authors.initials: J
authors.lastname: Leopold
authors.forename: Hollis
authors.initials: H
authors.lastname: Showalter
mesh_terms: D000215:Acylation / Q000187:drug effects*; D000477:Alkylating Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000477:Alkylating Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C067834:RB 6145; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole