肉桂酸和香豆素类衍生物的合成及其抗氧化性能的研究
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摘要
对天然产物进行结构修饰与改造是发现新药的重要手段和途径。肉桂酸和香豆素是两类非常重要的天然活性化合物。肉桂酸是一种在苯环上联有丙烯酸基团的化合物，广泛存在于自然界之中，具有多种生理活性，例如：治疗动脉粥样化，抗过敏，消炎，杀菌，抗氧化，抗癌，抗血栓形成和保护心脏等功能。肉桂酸类衍生物因其广泛的生理活性在临床上被广泛的应用。香豆素(Coumarin)，学名α-苯并吡喃酮，是顺式邻羟基肉桂酸的内酯，是一大类广泛存在于植物界中的香豆素类衍生物的母核，如蛇床子、独活、白芷、秦皮、等多种中草药中都含有香豆素类衍生物。香豆素类衍生物具有多种生理活性，比如：抗氧化性，抗HIV，抗细菌，抗癌等作用。因此，本文首先以N-苯乙基肉桂酰(CNPA)为母核合成一系列含羟基衍生物，讨论羟基及共轭体系对化合物抗氧化性能的影响；然后引入香豆素、三氮唑、1,4-二氢吡啶和吡啶合成一系列肉桂酸与香豆素衍生物，讨论其抗氧化活性与结构的构效关系。所取得的研究成果如下：
(1)以N-苯乙基肉桂酰胺(CNPA)为分子母核，对苯环进行结构修饰合成了6个CNPA衍生物。并通过不同的体外抗氧化模型的测试，包括化学体系法的二苯代苦味肼基自由基(DPPH)法、2,2-联氮-双-(3-乙基苯并噻唑啉-6-磺酸)二铵盐(ABTS+)法、galvinoxyl法、β-carotene-bleaching法和化学模拟的生物体系法中的Cu2+/GSH(谷胱甘肽)引发的DNA氧化损伤法和2,2-偶氮-二(2-脒基丙烷)盐酸盐(AAPH)引发的DNA氧化损伤法，讨论苯环取代基对化合物母核结构抗氧化性能的影响。结果发现：羟基的引入能够提高CNPA母核结构捕获ABTS+、DPPH和Galvinoxyl自由基、保护Gu2+/GSH和AAPH诱导的DNA氧化损伤、保护亚油酸自氧化的能力，说明羟基对化合物抗氧化性能有着重要的影响，尤其是邻苯二酚结构和邻羟基甲氧基结构能够显著提高化合物的抗氧化性能；而酰胺键、苯乙基及对羟基苯乙基对化合物抗氧化性能只有微弱影响，说明肉桂酸中的苯乙烯共轭体系在化合物抗氧化性能中起着重要的作用。
(2)将香豆素环引入到CNPA母核结构中，加大化合物的共轭体系，合成了一系列具有CNAP母核结构的香豆素衍生物。通过和上述相同的抗氧化活性测试方法表征化合物的抗氧性能，讨论其构效关系，结果发现：香豆素环的引入显著的提高了化合物捕获ABTS+自由基、保护OH和AAPH诱导的DNA氧化损伤的能力，尤其在计量因子n的计算当中，在没有邻苯二酚结构的情况下，化合物3f的n更高达24.96，说明香豆素环结构的引入，化合物共轭体系的增大对化合物的抗氧化性能有着重要的影响。
(3)为了验证共轭体系及取代基对化合物抗氧化性能的影响，在保持香豆素母环结构不变的情况下，将3-酰胺基用具有生物活性的三唑结构取代，合成一系列3-三唑香豆素类衍生物。通过对其抗氧化性能的研究，讨论其构效关系，结果发现：在捕获ABTS+自由基的测试实验中，化合物6f-i表现出了更强的抗氧化能力；在OH引发DNA氧化损伤测试实验中，三唑环上吸电子取代基和推电子取代基都能提高化合物的抗氧化性能，但吸电子取代基效果更好；在AAPH诱导的DNA氧化损伤测试实验中，含羟基取代基的3-三唑香豆素衍生物6d-i都具有抑制DNA氧化损伤的能力，而且所测n值均大于3，说明大共轭体系的引入以及羟基取代基都能提高了衍生物分子骨架的抗氧化性能。
(4)通过Hantzsch反应合成含有吡啶环大共轭体系的肉桂酸衍生物，通过对其抗氧化性能的研究，讨论与肉桂酸共轭的吡啶环对抗氧化性能的影响，结果发现：在OH引发DNA氧化损伤测试实验中，化合物2a-d和3a-d都表现出了良好的抗氧化性能，但是与苯环取代基没有必然联系，说明含有1,4二氢吡啶及吡啶肉桂酸衍生物分子骨干本身具有不错的抗氧化性能；通过AAPH诱导DNA氧化损伤测试实验，发现化合物中N-H均表现出良好的抗氧化性能；将化合物3a与FRTA相比较，发现3a的计量因子n大于FRTA的n值，验证了大的共轭体系能够提高化合物的抗氧化性能。
Structural modification and transformation of natural products is an importantapproach to discover new drugs. Cinnamic acid and coumarin are two important types ofbioactive natural compounds. Cinnamic acid possessing a benzene ring linked withacrylic group, is widely distributed in nature. Cinnamic acid derivatives exhibite a varietyof physiological activities, such as anti-atherogenic, anti-allergic, anti-inflammatory,antiseptic, antioxidant, anti-cancer, anti-thrombosis and heart-protecting functions.Because of its broad range of physiological activity, cinnamic acid derivatives isextensively used in clinical practice. Coumarin(α-benzo-pyranone), a lactone ofcis-hydroxyl-cinnamic acid, exists as nucleus of a large class of plant polyketides foundin osthol, heracleum hemsleyanum, angelica, cortex fraxini, peucedanum and many otherChinese medicinal herbs. Coumarin derivatives possess a variety of physiological activity,such as antioxidation, anti-HIV, antibacterial, anti-cancer effects. Therefore, in this study,a series cinnamoylphenethylamine (CNPA) derivatives were synthesized in order toinvestigate the influence of the number and the position of hydroxyl group andconjugation system on antioxidation. Then several series of derivatives containingcoumarin, triazole,1,4-dihydropyridine and pyridine were synthesized, and theirantioxidative activity were screaned for QSAR studies. The innovative research resultsachieved are as follows:
(1) Cinnamoylphenethylamine (CNPA) derivatives including feruloylphenethyl-amine (FRPA), caffeoylphenethylamine (CFPA), cinnamoyltyramine (CNTA), feruloyl-tyramine (FRTA) and caffeoyltyramine (CFTA) were synthesized in order to investigatethe influence of the number and position of hydroxyl group and the conjugation systemon Cu2+/glutathione(GSH) and2,2’-azobis(2-amidinopropane hydrochloride)(AAPH)indu-ced oxidation of DNA. The radical scavenging properties of these CNPA derivatives were also evaluated by trapping2,2’-azinobis(3-ethylbenzothiazoline-6-sulphonate) cationic radical(ABTS+),2,2’-diphenyl-1-picrylhydrazyl radical(DPPH) andgalvinoxyl radical. In addition, these CNPA derivatives were tested by linoleic acid(LH)-β-carotene-bleaching experiment. The chemical kinetics was employed to treat theresults from AAPH-induced oxidation of DNA and gave the order of antioxidant abilityas CFTA> CFPA> FRTA> FRPA. CFTA and CFPA also possessed high abilities toinhibit Cu2+/GSH-mediated degradation of DNA, whereas FRPA and FRTA can protectLH against the autooxidation efficiently. Finally, CFPA and FRPA exhibited high activityin trapping ABTS+, DPPH and galvinoxyl radicals. Therefore, the cinnamoyl groupbearing ortho-dihydroxyl or hydroxyl with ortho-methoxyl benefit DNA by CNPAderivatives. While hydroxyl in tyramine cannot enhance the radical-scavenging abilitiesof CNPA derivatives. This indicates radicals deriving from ortho-dihydroxyl group inCFTA can be stabilized by the conjugation system via resonance structure.
(2) A series of coumarin-3-acylamino derivatives containing phenethylamine moietyor tyramine moiety were synthesized and evaluated for their antioxidant activities by thesame experimental systems decribed as aboved. Among them, compounds3d-f weresynthesized for the first time, and the antioxidant activities of compounds2a,2b and3b-f were evaluated for the first time. We found that both hydroxyl and ortho-methoxygroups at A ring, hydroxyl group at B ring increase the protective abilities ofcoumarin-3-acylamino derivatives to protect DNA against OH-and AAPH-inducedoxidation, while decrease the protective abilities in Cu2+/GSH-induced oxidation system.The ortho-methoxyl group at A ring and the hydroxyl group at B ring possess high abilityto inhibit OH-induced oxidation of DNA. Furthermore, they play the major role intrapping ABTS+. It is worthy to note that the n value of compound3f is almost25, itmeans that big conjugation system of coumarin can significantly enhance the antioxidantactivites of compound3f.
(3) In order to verify the effects of conjugation system to antioxidative activities ofthe antioxidants, amide group was substituted by triazole, increased conjugation systemof compounds, series3-triazole coumarin derivatives were synthesized and their antioxidant properties were evaluated. Compound6f-i have a stronger ability to captureABTS+. By analyzing the results of3-triazole-coumarin derivatives6a-i on OH-induced DNA oxidation test, we found that electron-withdrawing group and electron-donating group can improve the antioxidant properties of these compounds, but theelectron-withdrawing group is superior. We found that the coumarin group bearinghydroxyl benefited for3-triazole coumarin derivatives to protect DNA againstAAPH-induced oxidation. Then we found that all the n value of6d-i were higher than3,I suggests that the big conjugation system of derivatives can significantly enhance theantioxidant activites of compounds.
(4) We synthesize cinnamic acid derivatives containing a large pyridine ring in orderto increase conjugation system through Hantzsch reaction. In the evluation theirantioxidant properties, we found that: both compound2a-d and3a-d have similarlyantioxidant activity to protect DNA against OH-induced oxidation, demonstrated that1,4-dihydropyridine and pyridine nucleus exhibit good resistance to oxidation and thesubstituents have little effects. In the AAPH-induced oxidative DNA damage, peptidebond can significantly enhance the antioxidant efficiency. Comparing the n value of ofFRTA, we found that n value of compound3a is greater than that of FRTA, indicates thata large conjugation system has a very important role to antioxidant properties ofcompounds.
(1)以N-苯乙基肉桂酰胺(CNPA)为分子母核，对苯环进行结构修饰合成了6个CNPA衍生物。并通过不同的体外抗氧化模型的测试，包括化学体系法的二苯代苦味肼基自由基(DPPH)法、2,2-联氮-双-(3-乙基苯并噻唑啉-6-磺酸)二铵盐(ABTS+)法、galvinoxyl法、β-carotene-bleaching法和化学模拟的生物体系法中的Cu2+/GSH(谷胱甘肽)引发的DNA氧化损伤法和2,2-偶氮-二(2-脒基丙烷)盐酸盐(AAPH)引发的DNA氧化损伤法，讨论苯环取代基对化合物母核结构抗氧化性能的影响。结果发现：羟基的引入能够提高CNPA母核结构捕获ABTS+、DPPH和Galvinoxyl自由基、保护Gu2+/GSH和AAPH诱导的DNA氧化损伤、保护亚油酸自氧化的能力，说明羟基对化合物抗氧化性能有着重要的影响，尤其是邻苯二酚结构和邻羟基甲氧基结构能够显著提高化合物的抗氧化性能；而酰胺键、苯乙基及对羟基苯乙基对化合物抗氧化性能只有微弱影响，说明肉桂酸中的苯乙烯共轭体系在化合物抗氧化性能中起着重要的作用。
(2)将香豆素环引入到CNPA母核结构中，加大化合物的共轭体系，合成了一系列具有CNAP母核结构的香豆素衍生物。通过和上述相同的抗氧化活性测试方法表征化合物的抗氧性能，讨论其构效关系，结果发现：香豆素环的引入显著的提高了化合物捕获ABTS+自由基、保护OH和AAPH诱导的DNA氧化损伤的能力，尤其在计量因子n的计算当中，在没有邻苯二酚结构的情况下，化合物3f的n更高达24.96，说明香豆素环结构的引入，化合物共轭体系的增大对化合物的抗氧化性能有着重要的影响。
(3)为了验证共轭体系及取代基对化合物抗氧化性能的影响，在保持香豆素母环结构不变的情况下，将3-酰胺基用具有生物活性的三唑结构取代，合成一系列3-三唑香豆素类衍生物。通过对其抗氧化性能的研究，讨论其构效关系，结果发现：在捕获ABTS+自由基的测试实验中，化合物6f-i表现出了更强的抗氧化能力；在OH引发DNA氧化损伤测试实验中，三唑环上吸电子取代基和推电子取代基都能提高化合物的抗氧化性能，但吸电子取代基效果更好；在AAPH诱导的DNA氧化损伤测试实验中，含羟基取代基的3-三唑香豆素衍生物6d-i都具有抑制DNA氧化损伤的能力，而且所测n值均大于3，说明大共轭体系的引入以及羟基取代基都能提高了衍生物分子骨架的抗氧化性能。
(4)通过Hantzsch反应合成含有吡啶环大共轭体系的肉桂酸衍生物，通过对其抗氧化性能的研究，讨论与肉桂酸共轭的吡啶环对抗氧化性能的影响，结果发现：在OH引发DNA氧化损伤测试实验中，化合物2a-d和3a-d都表现出了良好的抗氧化性能，但是与苯环取代基没有必然联系，说明含有1,4二氢吡啶及吡啶肉桂酸衍生物分子骨干本身具有不错的抗氧化性能；通过AAPH诱导DNA氧化损伤测试实验，发现化合物中N-H均表现出良好的抗氧化性能；将化合物3a与FRTA相比较，发现3a的计量因子n大于FRTA的n值，验证了大的共轭体系能够提高化合物的抗氧化性能。
Structural modification and transformation of natural products is an importantapproach to discover new drugs. Cinnamic acid and coumarin are two important types ofbioactive natural compounds. Cinnamic acid possessing a benzene ring linked withacrylic group, is widely distributed in nature. Cinnamic acid derivatives exhibite a varietyof physiological activities, such as anti-atherogenic, anti-allergic, anti-inflammatory,antiseptic, antioxidant, anti-cancer, anti-thrombosis and heart-protecting functions.Because of its broad range of physiological activity, cinnamic acid derivatives isextensively used in clinical practice. Coumarin(α-benzo-pyranone), a lactone ofcis-hydroxyl-cinnamic acid, exists as nucleus of a large class of plant polyketides foundin osthol, heracleum hemsleyanum, angelica, cortex fraxini, peucedanum and many otherChinese medicinal herbs. Coumarin derivatives possess a variety of physiological activity,such as antioxidation, anti-HIV, antibacterial, anti-cancer effects. Therefore, in this study,a series cinnamoylphenethylamine (CNPA) derivatives were synthesized in order toinvestigate the influence of the number and the position of hydroxyl group andconjugation system on antioxidation. Then several series of derivatives containingcoumarin, triazole,1,4-dihydropyridine and pyridine were synthesized, and theirantioxidative activity were screaned for QSAR studies. The innovative research resultsachieved are as follows:
(1) Cinnamoylphenethylamine (CNPA) derivatives including feruloylphenethyl-amine (FRPA), caffeoylphenethylamine (CFPA), cinnamoyltyramine (CNTA), feruloyl-tyramine (FRTA) and caffeoyltyramine (CFTA) were synthesized in order to investigatethe influence of the number and position of hydroxyl group and the conjugation systemon Cu2+/glutathione(GSH) and2,2’-azobis(2-amidinopropane hydrochloride)(AAPH)indu-ced oxidation of DNA. The radical scavenging properties of these CNPA derivatives were also evaluated by trapping2,2’-azinobis(3-ethylbenzothiazoline-6-sulphonate) cationic radical(ABTS+),2,2’-diphenyl-1-picrylhydrazyl radical(DPPH) andgalvinoxyl radical. In addition, these CNPA derivatives were tested by linoleic acid(LH)-β-carotene-bleaching experiment. The chemical kinetics was employed to treat theresults from AAPH-induced oxidation of DNA and gave the order of antioxidant abilityas CFTA> CFPA> FRTA> FRPA. CFTA and CFPA also possessed high abilities toinhibit Cu2+/GSH-mediated degradation of DNA, whereas FRPA and FRTA can protectLH against the autooxidation efficiently. Finally, CFPA and FRPA exhibited high activityin trapping ABTS+, DPPH and galvinoxyl radicals. Therefore, the cinnamoyl groupbearing ortho-dihydroxyl or hydroxyl with ortho-methoxyl benefit DNA by CNPAderivatives. While hydroxyl in tyramine cannot enhance the radical-scavenging abilitiesof CNPA derivatives. This indicates radicals deriving from ortho-dihydroxyl group inCFTA can be stabilized by the conjugation system via resonance structure.
(2) A series of coumarin-3-acylamino derivatives containing phenethylamine moietyor tyramine moiety were synthesized and evaluated for their antioxidant activities by thesame experimental systems decribed as aboved. Among them, compounds3d-f weresynthesized for the first time, and the antioxidant activities of compounds2a,2b and3b-f were evaluated for the first time. We found that both hydroxyl and ortho-methoxygroups at A ring, hydroxyl group at B ring increase the protective abilities ofcoumarin-3-acylamino derivatives to protect DNA against OH-and AAPH-inducedoxidation, while decrease the protective abilities in Cu2+/GSH-induced oxidation system.The ortho-methoxyl group at A ring and the hydroxyl group at B ring possess high abilityto inhibit OH-induced oxidation of DNA. Furthermore, they play the major role intrapping ABTS+. It is worthy to note that the n value of compound3f is almost25, itmeans that big conjugation system of coumarin can significantly enhance the antioxidantactivites of compound3f.
(3) In order to verify the effects of conjugation system to antioxidative activities ofthe antioxidants, amide group was substituted by triazole, increased conjugation systemof compounds, series3-triazole coumarin derivatives were synthesized and their antioxidant properties were evaluated. Compound6f-i have a stronger ability to captureABTS+. By analyzing the results of3-triazole-coumarin derivatives6a-i on OH-induced DNA oxidation test, we found that electron-withdrawing group and electron-donating group can improve the antioxidant properties of these compounds, but theelectron-withdrawing group is superior. We found that the coumarin group bearinghydroxyl benefited for3-triazole coumarin derivatives to protect DNA againstAAPH-induced oxidation. Then we found that all the n value of6d-i were higher than3,I suggests that the big conjugation system of derivatives can significantly enhance theantioxidant activites of compounds.
(4) We synthesize cinnamic acid derivatives containing a large pyridine ring in orderto increase conjugation system through Hantzsch reaction. In the evluation theirantioxidant properties, we found that: both compound2a-d and3a-d have similarlyantioxidant activity to protect DNA against OH-induced oxidation, demonstrated that1,4-dihydropyridine and pyridine nucleus exhibit good resistance to oxidation and thesubstituents have little effects. In the AAPH-induced oxidative DNA damage, peptidebond can significantly enhance the antioxidant efficiency. Comparing the n value of ofFRTA, we found that n value of compound3a is greater than that of FRTA, indicates thata large conjugation system has a very important role to antioxidant properties ofcompounds.
引文
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