School of Pharmacy, Department Farmaco-Biologico, University of Messina, Viale Annunziata, 98168 Messina, Italy.
Biochimie. 2010 Sep;92(9):1101-7. doi: 10.1016/j.biochi.2010.04.017. Epub 2010 Apr 28.
4-methylcoumarins that possess two hydroxyl groups ortho to each other in the benzenoid ring have shown to have excellent antioxidant and radical-scavenging properties in different experimental models. Furthermore, they cannot be metabolized by the liver P450 monoxygenases and thus cannot form 3,4-coumarin epoxides, which are believed to be mutagenic. Herein, we present a study on the structure activity relationship of eight synthetic 4-methylcoumarins, carried out by employing a series of different chemical cell-free tests. These compounds were tested by means of three assays involving one redox reaction with the oxidant (DPPH assay, ABTS.+ assay and FRAP). Other assays were employed to evaluate the antioxidant properties of the coumarins under investigation against NO, O2.- and HClO, which are some of the major reactive oxygen and nitrogen species causing damage in the human body. Finally, we have measured the protective capacity of these coumarins against the oxidative damage in a simple biomimetic model of phospholipid membranes. Our results confirm the good antioxidant activity of the 7,8-hydroxy-4-methylcoumarins. In general, their activity is not significantly affected by the introduction of an ethoxycarbonylmethyl or an ethoxycarbonylethyl moiety at the C3 position. A discrete antioxidant activity is retained also by the 7,8-diacetoxy-4-methylcoumarins, although they are less efficient than the corresponding 7,8-dihydroxy compounds. Furthermore, as demonstrated in the brine shrimp toxicity test, none of the tested coumarins significantly affect the larvae viability. Two of the 4-methylcoumarins (7,8-dihydroxy-4-methylcoumarin and 7,8-dihydroxy-3-ethoxycarbonylethyl-4-methylcoumarin), very interestingly, showed strong scavenging activities against the superoxide anion and were also very effective in protecting the lipid bilayer against peroxidation. On the basis of these findings, these 4-methylcoumarins may be considered as potential therapeutic candidates for pathological conditions characterized by free radical overproduction.
4-甲基香豆素在苯环的邻位上有两个羟基，在不同的实验模型中表现出极好的抗氧化和自由基清除特性。此外，它们不能被肝 P450 单加氧酶代谢，因此不能形成 3,4-香豆素环氧化物，而后者被认为是致突变的。在此，我们进行了一项关于 8 种合成 4-甲基香豆素的构效关系研究，采用了一系列不同的化学无细胞测试。通过三种涉及与氧化剂的氧化还原反应的测定（DPPH 测定法、ABTS.+测定法和 FRAP）对这些化合物进行了测试。其他测定法用于评估所研究的香豆素对 NO、O2.-和 HClO 的抗氧化特性，这些都是在人体内造成损害的主要活性氧和氮物种。最后，我们在简单的磷脂膜仿生模型中测量了这些香豆素对氧化损伤的保护能力。我们的结果证实了 7,8-羟基-4-甲基香豆素的良好抗氧化活性。一般来说，它们的活性不会因在 C3 位引入乙氧羰基甲基或乙氧羰基乙基而受到显著影响。7,8-二乙酰氧基-4-甲基香豆素也保留了离散的抗氧化活性，尽管它们的效率不如相应的 7,8-二羟基化合物高。此外，如盐水虾毒性试验所示，所测试的香豆素均不会显著影响幼虫的存活率。两种 4-甲基香豆素（7,8-二羟基-4-甲基香豆素和 7,8-二羟基-3-乙氧羰基乙基-4-甲基香豆素）非常有趣，它们对超氧阴离子具有很强的清除活性，并且对保护脂质双层免受过氧化也非常有效。基于这些发现，这些 4-甲基香豆素可能被认为是自由基过度产生的病理状况的潜在治疗候选物。
