Mechanism of isomerization of 4-propyl-o-quinone to its tautomeric p-quinone methide
Mechanism of isomerization of 4-propyl-o-quinone to its tautomeric p-quinone methide
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DOI：
10.1021/tx9500888
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发表时间：
1996-01-01
影响因子：
4.1
通讯作者：
Hu, LQ
中科院分区：
文献类型：
--
作者：
Bolton, JL;Wu, HM;Hu, LQ
在之前的研究中，我们发现邻醌类（3,5-环己二烯-1,2-二酮）可以异构化成对醌类（4-烷基-2,5-环己二烯-1- 1），其速率取决于对位置上取代基的类型[Iverson， S. L., Hu， L. Q., Vukomanovic， V., and Bolton， J. L. (1995) Chem]。中华毒物学杂志，8(5),537-544。在本研究中，我们探索了4-丙基-3,5-环己二烯-1,2-二酮（PQ）及其苯二氘类似物4-（1',1'-二氘丙基）-3,5-环己二烯-1,2-二酮（DPQ）的异构化反应机理。结果表明，该异构化反应是一般碱基催化的，这表明具有碱性侧链的蛋白质上的氨基酸可以在体内催化该反应。测定的Bronsted β值为0.23 +/- 0.02，与速率决定步骤中质子的转移一致。缓冲液稀释图生成的速率/pH曲线与氢氧根离子浓度（pH值为7.8 ~ 9）有关，表明碱催化作用存在。在pH 6 ~ 7.8范围内，反应不受pH的影响，说明在该pH区域内，当缓冲液浓度较低时，存在其他反应过程。用CD2取代苄基CH2可显著减缓异构化反应。通过测定PQ和DPQ中作为谷胱甘肽偶联物捕获的醌的量，确定了氘同位素对醌生成的动力学影响。同位素对产物生成的影响为5.5 +/- 0.6,37℃。这些数据进一步证明，在体内，邻醌类化合物可以被碱性残基催化生成亲电醌类化合物，而在苄基亚甲基上氘取代可以抑制该反应。
In previous work, we showed that o-quinones (3,5-cyclohexadiene-1,2-diones) can isomerize to p-quinone methides (4-alkyl-2,5-cyclohexadien-1-one) at rates which depend on the type of substituent at the para position [Iverson, S. L., Hu, L. Q., Vukomanovic, V., and Bolton, J. L. (1995) Chem. Res. Toxicol. 8, 537-544]. In the present investigation, we explored the mechanism of this isomerization reaction using 4-propyl-3,5-cyclohexadiene-1,2-dione (PQ) and its benzyl dideuterio analog 4-(1',1'-dideuteriopropyl)-3,5-cyclohexadiene-1,2-dione (DPQ). The results show that the isomerization reaction is general base-catalyzed, which suggests that amino acids on proteins with basic side chains could catalyze the reaction in vivo. The Bronsted beta value was determined to be 0.23 +/- 0.02, consistent with the transfer of a proton in the rate-determining step. The rate/pH profile generated from the buffer dilution plots showed dependence on hydroxide ion concentration from pH 7.8 to 9, indicative of base catalysis. From pH 6 to 7.8, the reaction was independent of pH, suggesting that other processes compete at low buffer concentration in this pH region. Substitution of the benzyl CH2 group with CD2 dramatically slows the isomerization reaction. The kinetic deuterium isotope effect on quinone methide formation was determined by measuring the amount of quinone methide trapped as GSH conjugates from PQ compared with DPQ. The isotope effect on product formation was 5.5 +/- 0.6, 37 degrees C. These data provide further evidence that formation of these electrophilic quinone methides from o-quinones could be catalyzed by basic residues in vivo and that the reaction could be inhibited by deuterium substitution at the benzyl methylene group.