Perlman M E, Dunn J A, Piscitelli T A, Earle J, Rose W C, Wampler G L, MacDiarmid J E, Bardos T J
Department of Medicinal Chemistry, State University of New York at Buffalo, Amherst 14260.
J Med Chem. 1991 Apr;34(4):1400-7. doi: 10.1021/jm00108a024.
In view of the in vivo demonstrated radiation-potentiating activities of several previously studied 2,2-dimethylphosphoraziridines, six new compounds incorporating the bis(2,2-dimethyl-1-aziridinyl)phosphinyl moiety, together with an electron-affinic group such as 2-nitroimidazole or nitrobenzyl, have been synthesized and tested (1) in vitro for ability to increase the effect of X-irradiation under hypoxic conditions on V-79 Chinese hamster lung fibroblast cells, (2) in vivo for antitumor activity in the absence of radiation against P388 leukemia in mice, and (3) in a preliminary experiment with compound 10 only, in combination with whole-body gamma-radiation, using the P388 leukemia mouse model for in vivo radiation-potentiating activity. The chemical-alkylating activities and hydrolytic behavior of these compounds, as well as their antitumor activities without radiation, were found to be comparable to those of other 2,2-dimethylphosphoraziridines, while their in vitro radiosensitizing activities were at low concentrations generally comparable to that of misonidazole, with compound 8 showing superior activity. At higher concentrations, only compound 10 was sufficiently soluble and nontoxic to the cells for evaluation in this assay. Thus, the bis(2,2-dimethyl-1-aziridinyl) phosphinyl moiety does not seem to have contributed to the hypoxic radiosensitizing activities (only to the cytotoxicities) of the electron-affinic moieties in this in vitro assay. In comparison, the prototype 2,2-dimethylphosphoraziridine, ethyl [bis(2,2-dimethyl-1-aziridinyl) phosphinyl]carbamate (AB-132), showed at nontoxic doses no radiosensitizing activity in this assay, and at cytotoxic doses increased the cell-killing effect of each given dose of X-radiation additively under both hypoxic and oxic conditions. Conversely, only the 2,2-dimethylphosphoraziridine moiety appeared to participate in the moderate "therapeutic radiation-potentiating" activity indicated by compound 10 in the in vivo experiment using the P388 leukemia model (on day 1), as the misonidazole standard was inactive in this nonhypoxic system. Clearly, the mechanism of the in vivo observed radiation-potentiating effect of AB-132 and other 2,2-dimethylphosphoraziridines is different from that of the hypoxic radiosensitizers, but the possible synergism between the two biologically active moieties of the new compounds could not be demonstrated with the experimental models so far employed.
鉴于几种先前研究的2,2 - 二甲基磷氮丙啶在体内已证实具有辐射增强活性，已合成并测试了六种新化合物，它们含有双（2,2 - 二甲基 - 1 - 氮丙啶基）膦酰基部分以及一个亲电子基团，如2 - 硝基咪唑或硝基苄基。（1）在体外测试其在缺氧条件下增强X射线辐射对V - 79中国仓鼠肺成纤维细胞作用的能力；（2）在体内测试其在无辐射情况下对小鼠P388白血病的抗肿瘤活性；（3）仅对化合物10进行初步实验，将其与全身γ辐射联合使用，采用P388白血病小鼠模型测试其体内辐射增强活性。发现这些化合物的化学烷基化活性、水解行为以及它们在无辐射情况下的抗肿瘤活性与其他2,2 - 二甲基磷氮丙啶相当，而它们在体外的放射增敏活性在低浓度时一般与米索硝唑相当，化合物8表现出更高的活性。在较高浓度下，只有化合物10足够可溶且对细胞无毒，可用于该试验的评估。因此，在该体外试验中，双（2,2 - 二甲基 - 1 - 氮丙啶基）膦酰基部分似乎对亲电子部分的缺氧放射增敏活性（仅对细胞毒性）没有贡献。相比之下，原型2,2 - 二甲基磷氮丙啶，乙基[双（2,2 - 二甲基 - 1 - 氮丙啶基）膦酰基]氨基甲酸酯（AB - 132），在无毒剂量下在该试验中没有放射增敏活性，而在细胞毒性剂量下，在缺氧和有氧条件下均能使每个给定剂量的X射线辐射的细胞杀伤作用呈相加增加。相反，在使用P388白血病模型的体内实验（第1天）中，只有2,2 - 二甲基磷氮丙啶部分似乎参与了化合物10所显示的适度“治疗性辐射增强”活性，因为米索硝唑标准品在这个非缺氧系统中没有活性。显然，AB - 132和其他2,2 - 二甲基磷氮丙啶在体内观察到的辐射增强作用机制与缺氧放射增敏剂不同，但就目前所采用的实验模型而言，无法证明新化合物的两个生物活性部分之间可能存在的协同作用。
