三种天然黄酮结构修饰及其生物活性研究
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摘要
黄酮类化合物作为一类重要的天然产物,其广泛存在于自然界中。目前的研究证实黄酮类化合物具有多种生物活性,如抗氧化、抗菌、抗肿瘤、抗病毒、抗炎等。
本论文以自然界中广泛分布的三种黄酮化合物即芹菜素、山奈酚和槲皮素为研究对象,依据前期预试结果对其进行结构修饰,分别得到了两个不同系列的黄酮衍生物,并对其进行了抗细菌、抗真菌、抗氧化和抗癌细胞增殖活性及其构效关系的研究。目的是为了寻找和发现具有更高生物活性且易于合成得到的黄酮类物质,为新的药物研发提供备选的先导化合物,同时为今后的结构优化和药物研发提供有力的理论基础。通过研究,本实验取得了以下主要成果：
1.采用全合成的方法得到了26个C-7和C-8位胺甲基取代的黄酮衍生物,同时通过结构修饰的方法得到了5个C-8位胺甲基取代的黄酮衍生物和5个C-7位含有胺基的黄酮衍生物,并经过核磁共振(NMR)和质谱(ESI-MS)等手段对其结构进行了表征。通过体外抗细菌和抗癌细胞增殖活性评价,结果发现,经过结构修饰得到的黄酮衍生物,其生物活性普遍高于全合成的黄酮衍生物。结合活性实验结果和天然黄酮的分子结构特点,本论文确定后续研究采用天然黄酮芹菜素、山奈酚和槲皮素作为底物,结构修饰位点集中在8位和7位。
2.采用先与二卤代烷发生O-烃基化反应,再和脂肪胺进行N-烃基化反应的方法合成了20个芹菜素的7-O位衍生物,同时通过先制备带有芳香胺基取代的卤代烷,再将其和母体黄酮在弱碱性条件下反应的方法合成了5个山奈酚的7-O位衍生物和5个槲皮素的7-O位衍生物,并通过核磁共振(NMR)和质谱(ESI-MS)等手段对其结构进行了表征。采用二倍梯度稀释法和平板转种法测定了这些化合物对2种革兰氏阳性菌(金黄色葡萄球菌和枯草芽孢杆菌)和2种革兰氏阴性菌(大肠杆菌和铜绿假单胞菌)的最小抑菌浓度(MIC)和最小杀菌浓度(MBC)。结果显示：具有脂环链结构的衍生物的抗细菌活性普遍高于含有脂肪链的衍生物。其中芹菜素衍生物对革兰氏阳性菌较敏感,其活性都比母体化合物芹菜素的好,含脂环链的衍生物(18g-18j和19g-19j)的最小抑菌浓度(MIC)均在1.95-7.81μg/mL,最小杀菌浓度(MBC)为3.91-15.61μg/mL.而山奈酚衍生物和槲皮素衍生物对革兰氏阴性菌的敏感性略高于革兰氏阳性菌,芳香胺苯环上带有吸电子基团的衍生物21a和23a表现出最强的抑制活性,超过了阳性对照四环素而与氨苄青霉素相当。通过生长速率法评价了此类化合物对番茄灰霉病原菌、棉花枯萎病原菌、马铃薯干腐病原菌等7种植物源病原菌的体外抗真菌活性。结果显示：测试浓度为100μg/mL时,衍生物均表现出强于母体化合物的抗真菌活性。其中芹菜素衍生物中,19i的活性相对较高,而山奈酚衍生物和槲皮素衍生物中,结构中含有强吸电子基团的21c和23c显示出最强的抑制率,其中23c对苹果炭疽病原菌和番茄早疫病原菌的抑制率超过了阳性对照恶霉灵。从MTT法检测此类衍生物对人源性宫颈癌细胞(HeLa)、人源性肝癌细胞(HepG2)、人源性肺癌细胞(A549)和人源性乳腺癌细胞(MCF-7)的结果中,我们发现：在芹菜素衍生物中,具有脂环链结构的衍生物抗癌细胞增殖活性整体较好,其中化合物19j表现出最强的活性。而山奈酚衍生物和槲皮素衍生物中,结构中含有吸电子基团的23c显示出最强的抑制作用。
3.通过Mannich反应得到了10个C-8位取代的胺甲基芹菜素衍生物,15个C-8位取代的胺甲基山奈酚衍生物和15个C-8位取代的胺甲基槲皮素衍生物,并通过核磁共振(NMR)和质谱(ESI-MS)等手段对其结构进行了表征。抗细菌活性结果显示：具有脂环链结构的衍生物整体活性较好,且对革兰氏阳性菌的抑制作用较高,其中化合物26o对金黄色葡萄球菌和枯草芽孢杆菌的MIC值最小为1.95μg/mL, MBC值为3.91μg/mL,与阳性对照四环素相当。体外抗7种植物源病原菌的结果表明,槲皮素衍生物整体表现出高于芹菜素衍生物和山奈酚衍生物的抑制率,且大部分含有取代基为脂环链状结构的衍生物的活性较好。采用DPPH自由基清除法测定了此类化合物的抗氧化能力,其中化合物26n的活性最强,其IC50值为93.8抗4种癌细胞增殖活性结果显示,大部分含有取代基为脂环链状结构的衍生物的活性较好,其中对于HeLa和HepG2细胞,26k的活性最强,分别为8μg/mL和6μg/mL,强于阳性对照5-氟尿嘧啶；而对A549和MCF-7细胞,活性最强的则是26o,与阳性对照5-氟尿嘧啶相当。
综上所述,本论文的研究对于开发抗菌剂及寻找安全、高效的抗肿瘤先导化合物有重要意义。7-O位黄酮衍生物具有较母体化合物强的生物活性,特别是山奈酚衍生物和槲皮素衍生物。C-8位黄酮衍生物具有比母体化合物较好的生物活性,特别是具有脂环链结构的衍生物显示出很强的生物活性。这些活性黄酮衍生物可以作为抗菌剂、抗氧化剂和抗癌药物深入研究的对象。
Flavonoids are an important class of natural products, which are widely found in nature. It was proved that flavonoids had a variety of biological activities, such as antioxidant, antibacterial, anti-tumor, anti-viral, and anti-inflammatory activity.
We synthesized two different series of flavonoid derivatives according to appropriate structural modifications on apigenin, kaempferol and quercetin, which were distributed widely. Then the in vitro bioactivities and structure-activity relationship were systematically evaluated to bacteria, plant pathogenic fungi, DPPH radical scavenging and cancer cell lines. The objective of this research was to search and find flavonoid compounds with higher bioactivities, simple structures and easy to synthesize. To provide for the new drug development candidate lead compounds and build theoretical foundation to subsequent structural optimation and medicinal development. According to our present results, the conclusions were made as follows.
1. Twenty-six C-7and C-8aminomethyl flavonoid derivatives were synthesized. Five C-8aminomethyl flavonoid derivatives and five flavonoid derivatives containing amine group on C-7were abtained by structural modification. The structural characterizations were determined by NMR,and ESI-MS. In vitro antibacterial and antiproliferative assay indicated compounds abtained by structural modification had higher activities than synthetic flavonoid compounds. Based on the experiment results and the molecular structure of the natural flavonoids, we determined the structural modification on C-7and C-8positions of apigenin, kaempferol, and quercetin.
2. Apigenin reacted with dihaloalkane, then with aliphatic amines. So, twenty apigenin7-O derivatives were gained. Meantime, five kaempferol7-O derivatives and five quercetin7-O derivatives were abtained according to different synthetic route. The chemical structures of these compounds were characterized using NMR, and ESI-MS. In vitro antibacterial activity against two Gram-positive bacteria(Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coliand Pseudomonas aeruginosa) of them was evaluated by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) method. The result showed that the activity of compounds with alicyclic chain substituent was higher than aliphatic chain substituent. Apigenin derivatives exhibited relatively better inhibition of Gram-positive bacteria than Gram-negative bacteria. And they all showed higher antibacterial activities than the parent apigenin. The MIC values of compounds with alicyclic chain substituent (18g-18j and19g-19j) were1.95-7.8μg/mL, and the MBC values of them were3.91-15.61μg/mL. However, the derivatives of kaempferol and quercetin displayed relatively higher antibacterial activities in vitro against Gram-negative strains than Gram-positive strains. Compounds21a and23a with aromatic amines having electron-withdrawing groups on its phenyl ring showed the strongest inhibitory activity, better than tetracycline and close to ampicillin. In vitro antifungal activity of these compounds was evaluated with the growth rate method against Botrytis cinerea Pers., Fusarium graminearum, Fusarium oxysporum f. sp. vasinfectum, Fusarium bulbigenum, Colletot Tichum Gloeosporioid.es, Alternaria solani, and Fusarium solani. The result showed that the activity of them was better than the parent compounds at the concentration of100μg/mL. Compound19i exhibited relatively higher activity in apigenin derivatives, and compounds21c and23c had the best inhibitory activity. The inhibitory ratios of23c against Colletot Tichum Gloeosporioides and Alternaria solani were higher than hymexazol. In vitro antiproliferative activity of compounds was detected on human cervical (HeLa), human hepatocellular liver (HepG2), human lung (A549), and human breast (MCF-7) cancer cells using MTT method. The activity of compounds with alicyclic chain substituent was better, compound19j showed the best activity in apigenin derivatives, and23c containing electron-withdrawing groups in its structure had the highest activity in kaempferol derivatives and quercetin derivatives.
3. Ten apigenin derivatives, fifteen kaempferol derivatives and fifteen quercetin derivatives containing aminomethyl groups on the C-8position were synthesized by Mannich reaction. The structures were elucidated by NMR, and ESI-MS. In vitro antibacterial activity indicated compounds with alicyclic chain substituent was better, and had relatively better inhibition of Gram-positive bacteria than Gram-negative bacteria. The MIC and MBC values of compound26o were1.95μg/mL and3.91μg/mL against Gram-positive bacteria, comparable with the positive control tetracycline. In vitro antifungal activity displayed quercetin derivatives were higher than apigenin derivatives and kaempferol derivatives, and most of compounds with alicyclic chain substituent were better. The antioxidant activity was determined using the DPPH radical scavenging assay. Compound26n showed the strongest activity with IC50of93.8μg/mL. The antiproliferative activities of the compounds were analyzed against four human cancer cell lines. Most of compounds with alicyclic chain substituent had the better activity. Compound26k displayed the strongest activity against HeLa and HepG2cells with the IC50of8μg/mLand6μg/mL, which were higher than the positive control5-FU. Compound26o had the strongest activity against A549and MCF-7 cells, comparable with5-FU.
In conclusion, this study in developing antibacterial agent and looking for a safe and efficient anti-cancer lead compounds are important. In7-O modified derivatives, kaempferol derivatives and quercetin derivatives had stronger bioactivities than its parent compounds. Compounds with alicyclic chain substituent in C-8modified derivatives showed the strongest activities. They can be developed as antimicrobial agent, antioxidant agent and anti-cancer drugs in the further study.
本论文以自然界中广泛分布的三种黄酮化合物即芹菜素、山奈酚和槲皮素为研究对象,依据前期预试结果对其进行结构修饰,分别得到了两个不同系列的黄酮衍生物,并对其进行了抗细菌、抗真菌、抗氧化和抗癌细胞增殖活性及其构效关系的研究。目的是为了寻找和发现具有更高生物活性且易于合成得到的黄酮类物质,为新的药物研发提供备选的先导化合物,同时为今后的结构优化和药物研发提供有力的理论基础。通过研究,本实验取得了以下主要成果：
1.采用全合成的方法得到了26个C-7和C-8位胺甲基取代的黄酮衍生物,同时通过结构修饰的方法得到了5个C-8位胺甲基取代的黄酮衍生物和5个C-7位含有胺基的黄酮衍生物,并经过核磁共振(NMR)和质谱(ESI-MS)等手段对其结构进行了表征。通过体外抗细菌和抗癌细胞增殖活性评价,结果发现,经过结构修饰得到的黄酮衍生物,其生物活性普遍高于全合成的黄酮衍生物。结合活性实验结果和天然黄酮的分子结构特点,本论文确定后续研究采用天然黄酮芹菜素、山奈酚和槲皮素作为底物,结构修饰位点集中在8位和7位。
2.采用先与二卤代烷发生O-烃基化反应,再和脂肪胺进行N-烃基化反应的方法合成了20个芹菜素的7-O位衍生物,同时通过先制备带有芳香胺基取代的卤代烷,再将其和母体黄酮在弱碱性条件下反应的方法合成了5个山奈酚的7-O位衍生物和5个槲皮素的7-O位衍生物,并通过核磁共振(NMR)和质谱(ESI-MS)等手段对其结构进行了表征。采用二倍梯度稀释法和平板转种法测定了这些化合物对2种革兰氏阳性菌(金黄色葡萄球菌和枯草芽孢杆菌)和2种革兰氏阴性菌(大肠杆菌和铜绿假单胞菌)的最小抑菌浓度(MIC)和最小杀菌浓度(MBC)。结果显示：具有脂环链结构的衍生物的抗细菌活性普遍高于含有脂肪链的衍生物。其中芹菜素衍生物对革兰氏阳性菌较敏感,其活性都比母体化合物芹菜素的好,含脂环链的衍生物(18g-18j和19g-19j)的最小抑菌浓度(MIC)均在1.95-7.81μg/mL,最小杀菌浓度(MBC)为3.91-15.61μg/mL.而山奈酚衍生物和槲皮素衍生物对革兰氏阴性菌的敏感性略高于革兰氏阳性菌,芳香胺苯环上带有吸电子基团的衍生物21a和23a表现出最强的抑制活性,超过了阳性对照四环素而与氨苄青霉素相当。通过生长速率法评价了此类化合物对番茄灰霉病原菌、棉花枯萎病原菌、马铃薯干腐病原菌等7种植物源病原菌的体外抗真菌活性。结果显示：测试浓度为100μg/mL时,衍生物均表现出强于母体化合物的抗真菌活性。其中芹菜素衍生物中,19i的活性相对较高,而山奈酚衍生物和槲皮素衍生物中,结构中含有强吸电子基团的21c和23c显示出最强的抑制率,其中23c对苹果炭疽病原菌和番茄早疫病原菌的抑制率超过了阳性对照恶霉灵。从MTT法检测此类衍生物对人源性宫颈癌细胞(HeLa)、人源性肝癌细胞(HepG2)、人源性肺癌细胞(A549)和人源性乳腺癌细胞(MCF-7)的结果中,我们发现：在芹菜素衍生物中,具有脂环链结构的衍生物抗癌细胞增殖活性整体较好,其中化合物19j表现出最强的活性。而山奈酚衍生物和槲皮素衍生物中,结构中含有吸电子基团的23c显示出最强的抑制作用。
3.通过Mannich反应得到了10个C-8位取代的胺甲基芹菜素衍生物,15个C-8位取代的胺甲基山奈酚衍生物和15个C-8位取代的胺甲基槲皮素衍生物,并通过核磁共振(NMR)和质谱(ESI-MS)等手段对其结构进行了表征。抗细菌活性结果显示：具有脂环链结构的衍生物整体活性较好,且对革兰氏阳性菌的抑制作用较高,其中化合物26o对金黄色葡萄球菌和枯草芽孢杆菌的MIC值最小为1.95μg/mL, MBC值为3.91μg/mL,与阳性对照四环素相当。体外抗7种植物源病原菌的结果表明,槲皮素衍生物整体表现出高于芹菜素衍生物和山奈酚衍生物的抑制率,且大部分含有取代基为脂环链状结构的衍生物的活性较好。采用DPPH自由基清除法测定了此类化合物的抗氧化能力,其中化合物26n的活性最强,其IC50值为93.8抗4种癌细胞增殖活性结果显示,大部分含有取代基为脂环链状结构的衍生物的活性较好,其中对于HeLa和HepG2细胞,26k的活性最强,分别为8μg/mL和6μg/mL,强于阳性对照5-氟尿嘧啶；而对A549和MCF-7细胞,活性最强的则是26o,与阳性对照5-氟尿嘧啶相当。
综上所述,本论文的研究对于开发抗菌剂及寻找安全、高效的抗肿瘤先导化合物有重要意义。7-O位黄酮衍生物具有较母体化合物强的生物活性,特别是山奈酚衍生物和槲皮素衍生物。C-8位黄酮衍生物具有比母体化合物较好的生物活性,特别是具有脂环链结构的衍生物显示出很强的生物活性。这些活性黄酮衍生物可以作为抗菌剂、抗氧化剂和抗癌药物深入研究的对象。
Flavonoids are an important class of natural products, which are widely found in nature. It was proved that flavonoids had a variety of biological activities, such as antioxidant, antibacterial, anti-tumor, anti-viral, and anti-inflammatory activity.
We synthesized two different series of flavonoid derivatives according to appropriate structural modifications on apigenin, kaempferol and quercetin, which were distributed widely. Then the in vitro bioactivities and structure-activity relationship were systematically evaluated to bacteria, plant pathogenic fungi, DPPH radical scavenging and cancer cell lines. The objective of this research was to search and find flavonoid compounds with higher bioactivities, simple structures and easy to synthesize. To provide for the new drug development candidate lead compounds and build theoretical foundation to subsequent structural optimation and medicinal development. According to our present results, the conclusions were made as follows.
1. Twenty-six C-7and C-8aminomethyl flavonoid derivatives were synthesized. Five C-8aminomethyl flavonoid derivatives and five flavonoid derivatives containing amine group on C-7were abtained by structural modification. The structural characterizations were determined by NMR,and ESI-MS. In vitro antibacterial and antiproliferative assay indicated compounds abtained by structural modification had higher activities than synthetic flavonoid compounds. Based on the experiment results and the molecular structure of the natural flavonoids, we determined the structural modification on C-7and C-8positions of apigenin, kaempferol, and quercetin.
2. Apigenin reacted with dihaloalkane, then with aliphatic amines. So, twenty apigenin7-O derivatives were gained. Meantime, five kaempferol7-O derivatives and five quercetin7-O derivatives were abtained according to different synthetic route. The chemical structures of these compounds were characterized using NMR, and ESI-MS. In vitro antibacterial activity against two Gram-positive bacteria(Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coliand Pseudomonas aeruginosa) of them was evaluated by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) method. The result showed that the activity of compounds with alicyclic chain substituent was higher than aliphatic chain substituent. Apigenin derivatives exhibited relatively better inhibition of Gram-positive bacteria than Gram-negative bacteria. And they all showed higher antibacterial activities than the parent apigenin. The MIC values of compounds with alicyclic chain substituent (18g-18j and19g-19j) were1.95-7.8μg/mL, and the MBC values of them were3.91-15.61μg/mL. However, the derivatives of kaempferol and quercetin displayed relatively higher antibacterial activities in vitro against Gram-negative strains than Gram-positive strains. Compounds21a and23a with aromatic amines having electron-withdrawing groups on its phenyl ring showed the strongest inhibitory activity, better than tetracycline and close to ampicillin. In vitro antifungal activity of these compounds was evaluated with the growth rate method against Botrytis cinerea Pers., Fusarium graminearum, Fusarium oxysporum f. sp. vasinfectum, Fusarium bulbigenum, Colletot Tichum Gloeosporioid.es, Alternaria solani, and Fusarium solani. The result showed that the activity of them was better than the parent compounds at the concentration of100μg/mL. Compound19i exhibited relatively higher activity in apigenin derivatives, and compounds21c and23c had the best inhibitory activity. The inhibitory ratios of23c against Colletot Tichum Gloeosporioides and Alternaria solani were higher than hymexazol. In vitro antiproliferative activity of compounds was detected on human cervical (HeLa), human hepatocellular liver (HepG2), human lung (A549), and human breast (MCF-7) cancer cells using MTT method. The activity of compounds with alicyclic chain substituent was better, compound19j showed the best activity in apigenin derivatives, and23c containing electron-withdrawing groups in its structure had the highest activity in kaempferol derivatives and quercetin derivatives.
3. Ten apigenin derivatives, fifteen kaempferol derivatives and fifteen quercetin derivatives containing aminomethyl groups on the C-8position were synthesized by Mannich reaction. The structures were elucidated by NMR, and ESI-MS. In vitro antibacterial activity indicated compounds with alicyclic chain substituent was better, and had relatively better inhibition of Gram-positive bacteria than Gram-negative bacteria. The MIC and MBC values of compound26o were1.95μg/mL and3.91μg/mL against Gram-positive bacteria, comparable with the positive control tetracycline. In vitro antifungal activity displayed quercetin derivatives were higher than apigenin derivatives and kaempferol derivatives, and most of compounds with alicyclic chain substituent were better. The antioxidant activity was determined using the DPPH radical scavenging assay. Compound26n showed the strongest activity with IC50of93.8μg/mL. The antiproliferative activities of the compounds were analyzed against four human cancer cell lines. Most of compounds with alicyclic chain substituent had the better activity. Compound26k displayed the strongest activity against HeLa and HepG2cells with the IC50of8μg/mLand6μg/mL, which were higher than the positive control5-FU. Compound26o had the strongest activity against A549and MCF-7 cells, comparable with5-FU.
In conclusion, this study in developing antibacterial agent and looking for a safe and efficient anti-cancer lead compounds are important. In7-O modified derivatives, kaempferol derivatives and quercetin derivatives had stronger bioactivities than its parent compounds. Compounds with alicyclic chain substituent in C-8modified derivatives showed the strongest activities. They can be developed as antimicrobial agent, antioxidant agent and anti-cancer drugs in the further study.
引文
陈志卫,胡永洲,吴好好,蒋惠娣.2005.黄酮类化合物的合成及其血管舒张作用.药学学报.40(11)：1001-1007.
段新方,张站斌,段新红.2003.5,3’,4’-三羟基-6,7-二甲氧基黄酮的另法全合成.有机化学,23(4)：353-355.
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