title: Radiosensitizers of hypoxic mammalian cells. 1-(Hydroxyaminoalkyl)-substituted nitroimidazoles.
abstract: A series of novel 1-(hydroxyaminoalkyl)-substituted nitroimidazoles has been synthesized as potential radiosensitizers for hypoxic mammalian cells. These compounds were synthesized via N-(hydroxyalkyl)phthalimide nitroimidazole intermediates which, on reaction with hydrazine hydrate, yielded the corresponding amines. The intermediates were prepared by reacting the epoxide derived from nitroimidazole with phthalimide and/or the epoxide derived from phthalimide with the nitroimidazole. The method was used successfully for the preparation of 2-, 4- and 5-nitroimidazole derivatives. In a modification of this procedure, 1-(2-aminoethyl)-2-nitroimidazole has been prepared by a new route which avoids the use of aziridine. These agents were tested for cytotoxicity and radiosensitizing ability in vitro using Chinese hamster V79 cells. All of the 2-nitroimidazoles tested showed toxicity similar to that previously reported for misonidazole and Ro 03-8799 (1-(2-hydroxy-3-piperidinopropyl)-2-nitroimidazole), two compounds currently undergoing clinical evaluation. In addition, all the novel primary amines were shown to function as hypoxic cell radiosensitizers. The 2-nitroimidazole derivatives were the most efficient compounds to be examined and showed at least as much activity as misonidazole.
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D003412:Cricetulus; D008920:Misonidazole / Q000494:pharmacology; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C033815:pimonidazole; D008920:Misonidazole; D010100:Oxygen