Cashman J R, Liu Y
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
J Med Chem. 1991 Jul;34(7):2049-55. doi: 10.1021/jm00111a019.
Drugs which contain a thiol functionality may be enzymatically or nonenzymatically oxidized to reactive metabolites, some of which cause adverse reactions. The synthesis of disulfide prodrugs to obviate unwanted drug side effects requires the development of novel catalysis. Herein, we describe the synthesis, structure-activity relationship, and mechanism investigations of the oxidation of model thiophenols with isoalloxazine disulfide formation catalysts. m-Nitrothiophenol reacts with the electron-deficient 8-cyano-N-3-(mercaptoalkyl)-10-phenylisoalloxazines and non-electron-deficient N-3-(mercaptoalkyl)-10-methylisoalloxazines to produce m-nitrothiophenol disulfide. m-Nitrothiophenol reacts with electron-deficient 8-cyano-10-phenyl-3-isoalloxazinepentanoic acid or 10-methyl-3-isoalloxazinepentanoic acid to form m-nitrothiophenol disulfide at a reduced rate, or not at all, respectively. Of the substituted isoalloxazines studied, electron-deficient isoalloxazines containing an N-3-mercaptoalkyl side chain were most efficient at catalyzing m-nitrothiophenol disulfide formation. Non-electron-deficient isoalloxazines without an N-3-alkyl mercaptan side chain did not catalyze m-nitrothiophenol oxidation. Electron-deficient isoalloxazines without N-3-alkyl mercaptan side chains catalyzed m-nitrothiophenol oxidation at 1/20 the rate for isoalloxazine 5. From kinetic and product studies, the differences in catalytic activity of 1-10 were judged to be due to changes in the chemical properties of the isoalloxazines and the ability to stabilize intramolecular thiol attack on the C(4a)-N(5) bond of the isoalloxazine. Electron-deficient isoalloxazines may be useful catalysts for the syntheses of disulfide prodrugs.
含有硫醇官能团的药物可能会被酶促或非酶促氧化为活性代谢物，其中一些会引起不良反应。合成二硫键前药以消除不必要的药物副作用需要开发新型催化方法。在此，我们描述了以异咯嗪二硫化物形成催化剂氧化模型苯硫酚的合成、构效关系及机理研究。间硝基苯硫酚与缺电子的8-氰基-N-3-(巯基烷基)-10-苯基异咯嗪以及非缺电子的N-3-(巯基烷基)-10-甲基异咯嗪反应生成间硝基苯硫酚二硫化物。间硝基苯硫酚与缺电子的8-氰基-10-苯基-3-异咯嗪戊酸或10-甲基-3-异咯嗪戊酸反应，分别以较低速率或根本不生成间硝基苯硫酚二硫化物。在所研究的取代异咯嗪中，含有N-3-巯基烷基侧链的缺电子异咯嗪在催化间硝基苯硫酚二硫化物形成方面效率最高。没有N-3-烷基硫醇侧链的非缺电子异咯嗪不催化间硝基苯硫酚氧化。没有N-3-烷基硫醇侧链的缺电子异咯嗪催化间硝基苯硫酚氧化的速率是异咯嗪5的1/20。通过动力学和产物研究判断，1-10催化活性的差异是由于异咯嗪化学性质的变化以及稳定分子内硫醇对异咯嗪C(4a)-N(5)键攻击的能力不同。缺电子异咯嗪可能是合成二硫键前药的有用催化剂。
