Krol E S, Bolton J L
Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago 60612-7231, USA.
Chem Biol Interact. 1997 Apr 18;104(1):11-27. doi: 10.1016/s0009-2797(97)03763-0.
Numerous phenols and catechols are known to be substrates for tyrosinase. While the catalytic mechanism of phenol oxidation by tyrosinase has been well studied, little work has been done to determine the influence of substituents on the reaction. In the present investigation, we explored the effects of changing substituents at the 2 and 6 position on the mechanism of tyrosinase-catalyzed oxidation of 4-allyl and 4-propylphenols and catechols. We have previously demonstrated that tyrosinase initially oxidizes hydroxychavicol (4-allyl-catechol) to an o-quinone (3,5-cyclohexadien-1,2-dione) which because of the relatively acidic protons in the benzyl position, readily isomerizes to the tautomeric p-quinone methide (4-allylidene-2,5-cyclohexadien-1-one, QM) (Bolton et al., 1994). We have confirmed through GSH trapping studies that oxidation of 4-allylphenol by tyrosinase yields the same o-quinone GSH conjugates as hydroxychavicol. In contrast, the presence of additional ortho substituents dramatically alters the mechanism of tyrosinase-catalyzed oxidation of 4-alkylphenols. For example, eugenol (4-allyl-2-methoxyphenol), which possesses 1 ortho-methoxy substituents, is not oxidized to a o-quinone or a QM. However, when both ortho o-quinones or QMs which may be selectively toxic to the malignant melanocyte. Although mammalian tyrosinase is much more substrate specific compared to the mushroom tyrosinase used in this study [42], it should be possible to identify compounds which are substrates for the mammalian form but are otherwise oxidatively stable. In order to develop such target compounds an improved understanding of substituent effects on tyrosinase-catalyzed oxidation of catechols and phenols is necessary. This should for the development of strategies for therapeutic compounds that are selectively toxic toward melanoma.
已知许多酚类和儿茶酚类物质是酪氨酸酶的底物。虽然酪氨酸酶催化酚类氧化的机制已得到充分研究，但关于取代基对该反应的影响却鲜有研究。在本研究中，我们探讨了在4 - 烯丙基苯酚和儿茶酚以及4 - 丙基苯酚和儿茶酚的酪氨酸酶催化氧化机制中，改变2位和6位取代基所产生的影响。我们之前已经证明，酪氨酸酶最初将羟基查维酮（4 - 烯丙基儿茶酚）氧化为邻醌（3,5 - 环己二烯 - 1,2 - 二酮），由于苄基位置相对酸性的质子，其很容易异构化为互变异构的对醌甲基化物（4 - 烯丙叉基 - 2,5 - 环己二烯 - 1 - 酮，QM）（博尔顿等人，1994年）。我们通过谷胱甘肽捕获研究证实，酪氨酸酶催化氧化4 - 烯丙基苯酚产生的邻醌谷胱甘肽缀合物与羟基查维酮相同。相比之下，额外邻位取代基的存在显著改变了酪氨酸酶催化氧化4 - 烷基苯酚的机制。例如，丁香酚（4 - 烯丙基 - 2 - 甲氧基苯酚），它有一个邻位甲氧基取代基，不会被氧化为邻醌或QM。然而，当两个邻位……邻醌或QM可能对恶性黑素细胞具有选择性毒性。尽管与本研究中使用的蘑菇酪氨酸酶相比，哺乳动物酪氨酸酶的底物特异性要强得多[42]，但应该有可能鉴定出作为哺乳动物形式底物但在其他方面氧化稳定的化合物。为了开发此类目标化合物，有必要更好地理解取代基对酪氨酸酶催化儿茶酚和酚类氧化的影响。这对于开发对黑色素瘤具有选择性毒性的治疗性化合物的策略应该是有帮助的。
