Monge A, Palop J A, López de Ceráin A, Senador V, Martínez-Crespo F J, Sainz Y, Narro S, García E, de Miguel C, González M
CIFA, Department of Medicinal Chemistry, Universidad de Navarra, Pamplona, Spain.
J Med Chem. 1995 May 12;38(10):1786-92. doi: 10.1021/jm00010a023.
Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substitutents in the 6- and/or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxides have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V). The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 63, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.
缺氧细胞是实体瘤而非正常组织的常见特征，对抗癌药物和放射治疗均具有抗性。因此，鉴定对缺氧细胞具有选择性毒性的药物是抗癌化疗的一个重要目标。苯并三嗪二 - N - 氧化物（SR 4233，替拉扎明）已被证明是一种对缺氧细胞有效的选择性细胞毒素。由于替拉扎明的生物还原活化被认为是由于存在1,4 - 二 - N - 氧化物部分，因此合成了一系列在6 - 和/或7 - 位具有一系列供电子和吸电子取代基的3 - 氨基喹喔啉 - 2 - 甲腈1,4 - 二 - N - 氧化物，并评估了其对缺氧细胞的毒性。喹喔啉二 - N - 氧化物和替拉扎明的电化学研究表明，随着6(7) - 取代基吸电子性质的增加，还原电位变得更正，化合物更容易被还原。除了未取代的6a和6,7 - 二甲基衍生物6c外，喹喔啉二 - N - 氧化物的还原电位明显比替拉扎明更正（Epc -0.90 V）。对培养细胞最有效的细胞毒素是6,7 - 二氯和6,7 - 二氟衍生物6i和6l，其效力比替拉扎明高30倍。6(7) - 氟和6(7) - 氯化合物6e和6h表现出最大的缺氧选择性。其中四种化合物63、6f、6h和6i在体外杀死了多细胞肿瘤球体的内部细胞。在体内，Balb/c小鼠耐受的这四种化合物的剂量是替拉扎明剂量的两倍。这项研究表明，喹喔啉1,4 - 二 - N - 氧化物可以提供有用的缺氧选择性治疗药物。
