Wardman P, Priyadarsini K I, Dennis M F, Everett S A, Naylor M A, Patel K B, Stratford I J, Stratford M R, Tracy M
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Br J Cancer Suppl. 1996 Jul;27:S70-4.
Pulse radiolysis was used to generate radicals from one electron reduction of 1,2,4-benzotriazine-1,4-dioxides (derivatives of tirapazamine), and of imidazo [1,2-a]quinoxaline-4-oxides (analogues of RB90740), which have selective toxicity towards hypoxic cells. Radicals from the mono N-oxides (from the latter compounds) react with oxygen approximately 10-40 times faster than does the tirapazamine radical. Radicals from the tirapazamine analogues studied react with oxygen up to approximately 10 times slower than tirapazamine radicals. The quinoxaline N-oxide radicals are involved in prototropic equilibria with pK(a) values (5.5 to 7.4) spanning that reported for tirapazamine (6.0). Generation of radicals radiolytically in the presence of H donors (formate, 2-propanol, deoxyribose) indicate a chain reaction ascribed to H abstraction by the drug radical. The protonated drug radical is much more reactive than the radical anion (H abstraction rate constant approximately equal to 10(2) - 10(3) dm3 mol-1 s-1). Chain termination is ascribed to drug radical-radical reactions, i.e. radical stability in anoxia, with rate constants 2k approximately equal to 1 x 10(7) to 2 x 10(8) dm3 mol-1 s-1 at pH approximately 7.4. Estimates of the reduction potentials of the drug-radical couples in water at pH 7 for two of the mono-N-oxides were in the range-0.7 to 0.8 V vs NHE at pH 7.
脉冲辐解用于通过对1,2,4 - 苯并三嗪 - 1,4 - 二氧化物（替拉扎明的衍生物）和咪唑并[1,2 - a]喹喔啉 - 4 - 氧化物（RB90740的类似物）进行单电子还原产生自由基，这些化合物对缺氧细胞具有选择性毒性。单N - 氧化物（来自后一种化合物）产生的自由基与氧反应的速度比替拉扎明自由基快约10 - 40倍。所研究的替拉扎明类似物产生的自由基与氧反应的速度比替拉扎明自由基慢约10倍。喹喔啉N - 氧化物自由基参与质子转移平衡，其pK(a)值（5.5至7.4）涵盖了替拉扎明报道的pK(a)值（6.0）。在H供体（甲酸盐、2 - 丙醇、脱氧核糖）存在下通过辐射分解产生自由基表明存在归因于药物自由基夺取H的链反应。质子化的药物自由基比自由基阴离子的反应性高得多（夺取H的速率常数约等于10(2) - 10(3) dm3 mol-1 s-1）。链终止归因于药物自由基 - 自由基反应，即在缺氧条件下自由基的稳定性，在pH约为7.4时，速率常数2k约等于1×10(7)至2×10(8) dm3 mol-1 s-1。对两种单N - 氧化物在pH 7的水中药物 - 自由基对的还原电位估计值相对于pH 7的标准氢电极在-0.7至0.8 V范围内。
