Palmer B D, Wilson W R, Cliffe S, Denny W A
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
J Med Chem. 1992 Aug 21;35(17):3214-22. doi: 10.1021/jm00095a018.
Nitroaniline mustards have potential as hypoxia-selective cytotoxic agents, with reductive metabolism activating the nitrogen mustard by converting the electron-withdrawing nitro group to an electron-donating hydroxylamine or amine. However, the parent compounds have poor aqueous solubility, and their potencies are limited by low reduction potentials (E1/2 ca. -600 mV versus the normal hydrogen electrode) and corresponding slow rates of nitro reduction. To address these limitations, a series of 4-nitroaniline mustards bearing hydrophilic side chains attached via an electron-withdrawing carboxamide group was prepared and evaluated for hypoxia-selective cytotoxicity against Chinese hamster cell lines. The N-[(N,N-dimethylamino)ethyl]carboxamide derivatives proved to have excellent aqueous solubility and improved cytotoxic potency, but their reduction potentials, while higher than the non-carboxamide compounds, were still low and little selectivity for hypoxic cells were observed. A series of carboxamides of 2,4-dinitroaniline mustard was also prepared. These compounds had reduction potentials in the desired range (E1/2 ca. -450 mV by cyclic voltammetry) and were more toxic to hypoxic than aerobic UV4 cells. The most selective compounds were 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (20, SN 23862) and its water-soluble N-[(N,N-dimethylamino)ethyl]carboxamide analogue. These showed selectivities of 60- to 70-fold for hypoxic UV4 cells. The selectivity of 20 was much superior to that of its aziridine analogue (23, CB 1954), which was only 3.6-fold more toxic to hypoxic than oxic cells in the same system. Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase). Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for its higher hypoxic selectivity than that of 23.
硝基苯胺氮芥有潜力成为缺氧选择性细胞毒剂，其还原代谢通过将吸电子的硝基转化为给电子的羟胺或胺来激活氮芥。然而，母体化合物的水溶性较差，其效力受到低还原电位（相对于标准氢电极，E1/2约为 -600 mV）以及相应的硝基还原速率缓慢的限制。为了解决这些限制，制备了一系列通过吸电子的甲酰胺基团连接亲水性侧链的4 - 硝基苯胺氮芥，并评估了它们对中国仓鼠细胞系的缺氧选择性细胞毒性。N - [（N，N - 二甲基氨基）乙基]甲酰胺衍生物被证明具有优异的水溶性和提高的细胞毒性效力，但其还原电位虽然高于非甲酰胺化合物，但仍然较低，并且对缺氧细胞几乎没有选择性。还制备了一系列2,4 - 二硝基苯胺氮芥的甲酰胺。这些化合物的还原电位在所需范围内（通过循环伏安法测定，E1/2约为 -450 mV），并且对缺氧的UV4细胞比需氧的更具毒性。最具选择性的化合物是5 - [N，N - 双（2 - 氯乙基）氨基] - 2,4 - 二硝基苯甲酰胺（20，SN 23862）及其水溶性N - [（N，N - 二甲基氨基）乙基]甲酰胺类似物。这些对缺氧的UV4细胞显示出60至70倍的选择性。20的选择性远优于其氮丙啶类似物（23，CB 1954），在同一系统中，后者对缺氧细胞的毒性仅比对有氧细胞高3.6倍。对于大鼠Walker肿瘤细胞的主要需氧硝基还原酶NAD（P）H：醌氧化还原酶（DT黄递酶），化合物20是比CB 1954效率低得多的底物。DT黄递酶对20缺乏需氧生物活化作用可能是其比23具有更高缺氧选择性的原因。
