Jabbari Atena, Sadeghian Hamid, Salimi Alireza, Mousavian Mina, Seyedi Seyed M, Bakavoli Mehdi
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Chem Biol Drug Des. 2016 Sep;88(3):460-9. doi: 10.1111/cbdd.12779. Epub 2016 Jun 6.
15-lipo-oxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. In this study, a series of allyl and prenyl dimethoxybenzenes were synthesized and their inhibitory potency against soybean 15-Lipo-oxygenase (L1; EC 1,13,11,12) was determined. Among the synthetic compounds, 2,6-dimethoxy-1-isopentenyl-4-methylbenzene, 2,6-dimethoxy-1-geranyl-4-methylbenzene, and 2,6-dimethoxy-1-farnesyl-4-methylbenzene showed the most potent inhibitory activity with IC50 values of 7.6, 5.3, and 0.52 μm, respectively. For some of the compounds, SAR studies showed acceptable relationship between inhibitory potency and enzyme-ligand interactions. Radical scavenging assessment results apart from the SAR studies indicate that electronic properties are the major factors for lipo-oxygenase inhibition potency of the mentioned compounds. Based on the theoretical studies, it was suggested that CH…O intramolecular hydrogen bond between ortho-methoxy oxygen and methine hydrogen atoms is one of the major factors in the stability of 2,6-dimethoxyallyl(or prenyl)benzenes radical via the planarity fixation between phenyl and allyl (or prenyl) pi orbitals.
15-脂氧合酶是动植物中能够对不饱和脂肪酸进行过氧化反应的含铁蛋白质之一。在哺乳动物中，这些酶在炎症、过敏反应以及某些癌症形成过程中的关键作用已得到证实。酶的重要性促使了机理研究、产物分析以及抑制剂合成等方面的发展。在本研究中，合成了一系列烯丙基和异戊二烯基二甲氧基苯，并测定了它们对大豆15-脂氧合酶（L1；EC 1,13,11,12）的抑制效力。在这些合成化合物中，2,6-二甲氧基-1-异戊烯基-4-甲基苯、2,6-二甲氧基-1-香叶基-4-甲基苯和2,6-二甲氧基-1-法尼基-4-甲基苯表现出最强的抑制活性，其IC50值分别为7.6、5.3和0.52μm。对于某些化合物，构效关系研究表明抑制效力与酶-配体相互作用之间存在可接受的关系。除构效关系研究外，自由基清除评估结果表明电子性质是上述化合物脂氧合酶抑制效力的主要因素。基于理论研究，有人提出邻甲氧基氧原子与次甲基氢原子之间的CH…O分子内氢键是通过苯基与烯丙基（或异戊二烯基）π轨道之间的平面固定作用使2,6-二甲氧基烯丙基（或异戊二烯基）苯自由基稳定的主要因素之一。
