3-Nitro-1,2,4-triazoles as hypoxia-selective agents.
A series of 1-alkyl-3-nitro-1,2,4-triazoles has been prepared and assessed in vitro as radiosensitizers of hypoxic cells and as bioreductive cytotoxins. The differential hypoxic:aerobic cytotoxicities of representative compounds have been determined and compared with analogous 2-nitroimidazoles. It is found that the 3-nitrotriazoles are considerably less effective than the corresponding 2-nitroimidazole derivatives. This result includes dual-function nitrotriazoles where potential alkylating moieties have been incorporated into the molecule. In contrast, the 3-nitrotriazoles show similar or slightly improved radiosensitizing efficiency, in accord with their redox behaviour, and significantly lower chronic aerobic toxicity compared with the corresponding 2-nitroimidazoles. On the basis of a derived in vitro therapeutic ratio, 1-(3-nitro-1,2,4-triazol-l-yl)-3-piperidino-2-propanol (8) has been identified as particularly active and warrants further evaluation as a hypoxic cell radiosensitizer in vivo.
Jenkins
T C
TC
CRC Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, UK.
Stratford
I J
IJ
Stephens
M A
MA
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
D011838:Radiation-Sensitizing Agents; D014230:Triazoles