3-Nitro-1,2,4-triazoles as hypoxia-selective agents.
3-Nitro-1,2,4-triazoles as hypoxia-selective agents.
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发表时间：
1989-08
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通讯作者：
T. C. Jenkins;I. Stratford;M. Stephens
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作者：
T. C. Jenkins;I. Stratford;M. Stephens
制备了一系列1-烷基-3-硝基-1,2,4-三唑，并对其作为缺氧细胞的放射增敏剂和生物还原性细胞毒素进行了体外评价。已测定了具有代表性的化合物的不同氧氧细胞毒性，并与类似的2-硝基咪唑进行了比较。结果表明，3-硝基三唑的药效明显低于相应的2-硝基咪唑衍生物。该结果包括双功能硝基三唑，其中潜在的烷基化部分已纳入分子。相比之下，3-硝基三唑表现出相似或略有改善的放射增敏效率，与其氧化还原行为一致，并且与相应的2-硝基咪唑相比，其慢性有氧毒性显着降低。根据衍生的体外治疗比，1-（3-硝基-1,2,4-三唑-1 -基）-3-胡椒酰-2-丙醇(8)已被确定为特别有效，值得进一步评估作为体内缺氧细胞放射增敏剂。
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.