title: A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): the cycloalkylaziridines.
abstract: A series of compounds related to alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069, 1) were synthesized and evaluated as selective hypoxic cell cytotoxic agents and as radiosensitizers. The aziridine moiety was replaced with a number of other potential alkylating groups including cycloalkylaziridines and azetidines. The data indicated that modification of the aziridine of 1 resulted in a substantial decrease in the ability of the compounds to selectively kill hypoxic cells. However, these modifications did not affect the compounds' in vitro radiosensitizing activity since many of the derivatives were as potent as 1. All of the compounds that were evaluated in vivo were less toxic than 1, and several members of this series had significant activity. The best compound was trans-alpha-[[(4-bromotetrahydro-2H-pyran-3-yl) amino]methyl]-2-nitro-1H-imidazole-1-ethanol (18), which, due to its activity and log P value, is a candidate for additional in vivo studies.
authors.affiliation: Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: M J
authors.initials: MJ
authors.lastname: Suto
authors.forename: M A
authors.initials: MA
authors.lastname: Stier
authors.forename: L M
authors.initials: LM
authors.lastname: Werbel
authors.forename: C M
authors.initials: CM
authors.lastname: Arundel-Suto
authors.forename: W R
authors.initials: WR
authors.lastname: Leopold
authors.forename: W E
authors.initials: WE
authors.lastname: Elliott
authors.forename: J S
authors.initials: JS
authors.lastname: Sebolt-Leopold
mesh_terms: D000818:Animals; D001388:Aziridines / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D005354:Fibrosarcoma / Q000532:radiotherapy; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D010100:Oxygen / Q000008:administration & dosage; D011714:Pyrans / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D001388:Aziridines; D009593:Nitroimidazoles; D011714:Pyrans; D011838:Radiation-Sensitizing Agents; C070476:(((4-bromotetrahydro-2H-pyran-3-yl)amino)methyl)-2-nitro-1H-imidazole-1-ethanol; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole; D010100:Oxygen