School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Molecules. 2022 Jan 26;27(3):812. doi: 10.3390/molecules27030812.
Hypoxia in tumors results in resistance to both chemotherapy and radiotherapy treatments but affords an environment in which hypoxia-activated prodrugs (HAP) are activated upon bioreduction to release targeted cytotoxins. The benzotriazine 1,4-di--oxide (BTO) HAP, tirapazamine (TPZ, ), has undergone extensive clinical evaluation in combination with radiotherapy to assist in the killing of hypoxic tumor cells. Although compound did not gain approval for clinical use, it has spurred on the development of other BTOs, such as the 3-alkyl analogue, SN30000, . There is general agreement that the cytotoxin(s) from BTOs arise from the one-electron reduced form of the compounds. Identifying the cytotoxic radicals, and whether they play a role in the selective killing of hypoxic tumor cells, is important for continued development of the BTO class of anticancer prodrugs. In this study, nitrone spin-traps, combined with electron spin resonance, give evidence for the formation of aryl radicals from compounds , and 3-phenyl analogues, compounds and , which form carbon C-centered radicals. In addition, high concentrations of DEPMPO (5-(diethoxyphosphoryl)-5-methyl-1-pyrroline -oxide) spin-trap the •OH radical. The combination of spin-traps with high concentrations of DMSO and methanol also give evidence for the involvement of strongly oxidizing radicals. The failure to spin-trap methyl radicals with PBN (--butylphenylnitrone) on the bioreduction of compound , in the presence of DMSO, implies that free •OH radicals are not released from the protonated radical anions of compound . The spin-trapping of •OH radicals by high concentrations of DEPMPO, and the radical species arising from DMSO and methanol give both direct and indirect evidence for the scavenging of •OH radicals that are involved in an intramolecular process. Hypoxia-selective cytotoxicity is not related to the formation of aryl radicals from the BTO compounds as they are associated with high aerobic cytotoxicity.
肿瘤中的缺氧会导致化疗和放疗的耐药性，但为缺氧激活前药 (HAP) 提供了一个环境，这些前药在生物还原后被激活，释放靶向细胞毒素。苯并三嗪 1,4-二氧化物 (BTO) HAP，替拉扎胺（TPZ，），已在与放疗联合的广泛临床评估中进行，以协助杀死缺氧肿瘤细胞。尽管化合物 未获得临床使用批准，但它推动了其他 BTO 的开发，例如 3-烷基类似物 SN30000，。人们普遍认为，BTO 类化合物的细胞毒素来自于化合物的单电子还原形式。确定细胞毒性自由基，以及它们是否在缺氧肿瘤细胞的选择性杀伤中发挥作用，对于继续开发 BTO 类抗癌前药非常重要。在这项研究中，氮氧自由基捕获剂与电子自旋共振相结合，为化合物 、 和 3-苯基类似物化合物 和 形成芳基自由基提供了证据，这些自由基形成碳 C 中心自由基。此外，高浓度的 DEPMPO（5-(二乙氧基膦酰基)-5-甲基-1-吡咯啉 -N-氧化物）自旋捕获 •OH 自由基。高浓度 DMSO 和甲醇与自旋捕获剂的结合也证明了强氧化性自由基的参与。在 DMSO 存在下，化合物 的生物还原过程中，用 PBN（--丁基苯氮酮）未能捕获甲基自由基，这意味着质子化的自由基阴离子不会从化合物 中释放出游离的 •OH 自由基。高浓度的 DEPMPO 对 •OH 自由基的自旋捕获，以及来自 DMSO 和甲醇的自由基种类，为涉及分子内过程的 •OH 自由基的清除提供了直接和间接证据。缺氧选择性细胞毒性与 BTO 化合物形成芳基自由基无关，因为它们与高需氧细胞毒性有关。
