title: Synthesis and evaluation of a series of 3,5-disubstituted benzisoxazole-4,7-diones. Potent radiosensitizers in vitro.
abstract: A series of 3,5-disubstituted-2,1-benzisoxazole-4,7-diones was synthesized and evaluated as radiosensitizers both in vitro and in vivo. These compounds were designed as non-nitro electron-affinic agents in an effort to alleviate some of the toxicities seen with the 2-nitroimidazole radiosensitizers evaluated in the clinic. Several compounds in this series were potent radiosensitizers in vitro, with sensitizer enhancement ratios of 2.0-2.3 at concentrations less than 0.5 mM. Compounds with potent in vitro activity were also evaluated in vivo. However, none of these compounds showed radiosensitizing activity in vivo. The reduction potentials of these compounds were determined by cyclic voltammetry and compared to other electron-affinic radiosensitizers. In general, the reduction potentials of this series of compounds was slightly more positive than the 2-nitroimidazoles, but they fell within the range postulated as acceptable to yield in vivo activity. The results suggest that factors other than reduction potential may be responsible for the lack of in vivo radiosensitizing activity observed for this class of radiosensitizers.
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: R T
authors.initials: RT
authors.lastname: Winters
authors.forename: W R
authors.initials: WR
authors.lastname: Turner
authors.forename: C D
authors.initials: CD
authors.lastname: Pinter
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; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007555:Isoxazoles; D011838:Radiation-Sensitizing Agents