title: Aziridinyl nitropyrroles and nitropyrazoles as hypoxia-selective cytotoxins and radiosensitizers.
abstract: A series of 1- and 2-substituted 4- and 5-nitropyrroles and 3- and 4-nitropyrazoles has been prepared and evaluated in vitro as radiosensitizers of hypoxic cells and as bioreductively-activated cytotoxins. Both the nitropyrroles and the nitropyrazoles were considerably less effective, based upon the differential between hypoxic and aerobic toxicity, than were similar 2-nitroimidazoles bearing alkylating moieties. The trends in radiosensitizing efficiency observed for both classes of drugs corresponded with their one-electron reduction potentials (E1(7] as measured by pulse radiolysis, although they were generally more effective than predicted from previous correlations of E1(7] with sensitizing efficacy and reactivities. Furthermore, the enhancement of sensitizing efficiency by the incorporation of alkylating groups is considerably greater than has been observed for nitroimidazoles. alpha-[(1-Aziridinyl)methyl]-3-nitropyrazole- 1-ethanol (10, E1(7) = -456 mV) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25, E1(7) = -326 mV) were the most effective radiosensitizers in vitro. Only 3-[cis-2,3-dimethyl-1-aziridinyl) methyl)-1-oxo-3,4-dihydro-6-nitro-1-H-pyrrolo [2,1-c] oxazine (22) and methyl 5-nitro-1-(cyclopropylcarbonyl)pyrrole-2-carboxylate (25) showed significant bioreductively-activated cytotoxicity, with differentials of 3.5. Although these differential toxicities were coupled with significantly lower aerobic toxicity compared with similar 2-nitroimidazoles, this series was not deemed effective enough to warrant further evaluation. The electron affinity and radiosensitization could be manipulated by chemical design but hypoxia-selectivity was not clearly related to these properties.
authors.affiliation: MRC Radiobiology Unit, Chilton, Didcot, Oxon, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Naylor
authors.forename: M A
authors.initials: MA
authors.lastname: Stephens
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: A
authors.initials: A
authors.lastname: Keohane
authors.forename: P
authors.initials: P
authors.lastname: O'Neill
authors.forename: M D
authors.initials: MD
authors.lastname: Threadgill
authors.forename: P
authors.initials: P
authors.lastname: Webb
authors.forename: E M
authors.initials: EM
authors.lastname: Fielden
authors.forename: G E
authors.initials: GE
authors.lastname: Adams
mesh_terms: D000818:Animals; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003603:Cytotoxins / Q000737:chemistry; D005609:Free Radicals; D000860:Hypoxia; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology; D011048:Polarography; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry
chemical_list: D001388:Aziridines; D003603:Cytotoxins; D005609:Free Radicals; D009574:Nitro Compounds; D011720:Pyrazoles; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents