资源植物朝鲜槐的化学成分、生物活性及其质量控制研究
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摘要
朝鲜槐(Maackia amurensis Rupr.et Maxim.)为豆科(Leguminosae)马鞍树属(Maackia Rupr.et Maxim)植物,主要分布于我国东北,是东北植物区系豆科唯一古老的特有种。民间将其树皮作为祛风湿、镇痛、消炎和止血药,用来治疗肿瘤、胆囊炎、瘀血肿痛、风湿性关节炎、溃疡等症。国内有关朝鲜槐的化学成分及药理活性研究较少。为了开发利用这一民间药用植物资源,我们对辽宁产朝鲜槐树皮进行了化学成分、生物活性试验及其质量控制方面的研究。
从朝鲜槐树皮70%的乙醇提取物中,经过多种色谱分离手段分离得到54个化合物,通过理化性质及波谱分析鉴定了这些化合物的结构,其中包括9个新化合物,分别命名为:怀槐二氢黄酮A(1,maackiaflavanone A),怀槐二氢黄酮B(2,maackiaflavanone B),怀槐异黄酮(3,maackiaisoflavone),怀槐紫檀烷A(4,maackiapterocarpan A),怀槐紫檀烷B(5,maackiapterocarpan B),怀槐异黄酮苷(15,Maackiaisoflavonoside),怀槐色原酮(39,maackiachromone),(2S,3S)-7-甲氧基二氢黄酮醇(41),(-)-怀槐金雀花碱(48,(-)-maackiacytisine);45个已知化合物:abyssinone V(6),(-)-sigmoidin E(7),5-hydroxysophoranone(8),maackiaflavanone(9),abyssinone II(10),abyssinone IV(11),euchrenone b_1(12),ulexone B(13),ulexone A(14),Dalsympathetin(16),芒柄花苷(17),鸡黄豆素苷(18),染料木苷(19),Saikoisoflavonoside A(20),阿夫罗摩辛-7-O-β-D-呲喃葡萄糖苷(21),gehuain(22),Kushenol O(23),4',6-二甲氧基-异黄酮-7-O-β-D-芹糖-(1→6)-β-D-吡喃葡萄糖苷(24),鸢尾种苷(25),5-羟基-4'-甲氧基-异黄酮-7-O-β-D-葡萄糖-(1→6)-β-D-吡喃葡萄糖苷(26),4'-甲氧基.异黄酮-7-O-β-D-芹糖-(1→6)-β-D-吡喃葡萄糖苷(27),glycitin-6"-O-acetate(28),ononin-6"-O-acetate(29),7,5'-dihydroxy-3'-methoxyisoflavone(30),retusin-8-methylether(31),7,4'-dihydroxy-3'-methoxyisoflavone(32),di-O-methyldaidzein(33),染料木素(genistein,34),阿夫罗摩辛(afromosin,35),芒柄花黄素(formononetin,36),樱黄素(prunetin,37),鸡黄豆素(glycitein,38),(±)-2,3-dihydro-3,5-dihydroxy-7-methoxyflavone(40),3,4-二甲氧基咖啡酸酯(42),高丽槐素(43)和美迪紫檀素(44),对羟基苯甲酸乙酯(45),对甲氧基苯甲酸(46),对羟基苯甲醛(47),金雀花碱(cytisine,49),(±)-formylcytisine(50),N-(3-oxobutyl)cytisine(51),(-)-epibaptifoline(52),N-methylcytisine(53)和β-谷甾醇(54)。其中化合物6,7,10—14,16,21—24,26-28,30,31,40,45—47等21个化合物为首次从马鞍树属植物中分离得到;化合物8,32为首次从朝鲜槐植物中分离得到。
根据朝鲜槐树皮民间抗肿瘤功效,选择一些特征性成分进行了细胞毒活性筛选。采用MTT法测试7个异戊烯基二氢黄酮(1,2,6-9,11),3个异戊烯基异黄酮(3,12,14);3个紫檀烷(4,43,44);及具有代表性的异黄酮染料木素(34),对人宫颈癌HeLa细胞、人黑色素瘤A375S2细胞、人乳腺癌MCF-7细胞和人肝癌HepG2细胞的细胞毒活性,结果所有被测试化合物均显示不同程度的细胞毒作用,其中怀槐二氢黄酮B抑制A375S2细胞IC_50值为7.8μM,euchrenone b_1抑制HeLa细胞IC_50值为4.5μM。
我们还首次对1个异戊烯基二氢黄酮5-hydroxysophoranone(8),及2个紫檀烷:高丽槐素(43)、美迪紫檀素(44)进行了细胞色素P450氧化酶CYPlA2、CYP2C9、CYP3A4抑制活性筛选研究,结果均显示较强的抑制活性,其中(一)-medicarpin(44)抑制CYPlA2IC_50值为10.7μM。
为了控制朝鲜槐药材的质量,首次采用紫外分光光度法测定朝鲜槐树皮中总黄酮含量约7.0%。对朝鲜槐树皮药材进行了HPLC指纹图谱研究,首次建立了朝鲜槐树皮药材HPLC指纹图谱方法,以分离得到的化学对照品,对朝鲜槐药材指纹图谱中23个特征峰进行了标定,共指认了18个色谱峰,其中17个为异黄酮类化合物,并采用HPLC法对2批朝鲜槐树皮药材中4个异黄酮苷:染料木苷、鸢尾种苷、Saikoisoflavonoside A及新化合物怀槐异黄酮苷进行了含量测定,为朝鲜槐及其相关制剂的质量控制研究奠定了基础。
Maackia amurensis Rupr.et Maxim.,belongs to the Leaguminosae family,Maackia species, is a deciduous tree distributed widely in the north of China.The dried stem bark of M. amurensis has been used as folk medicine for the treatment of rheumatoid arthritis,pain,allay inflammation,stanch bleeding,etc.In our country,little research on the chemical constituents and pharmacological activities of M.amurensis has been reported.For further development of this medicinal plant material,we conducted research on the chemical constituents,bioactivity and quality control of the stem bark of M.amurensis.
To study the chemical constituents of the M.amurensis,the constituents were isolated by various chromatography methods and the structures were elucidated on the basis of chemical and spectroscopic data.54 compounds were isolated from the 70%ethanol extract,including 9 new compounds:maackiaflavanone A(1),maackiaflavanone B(2),maackiaisoflavone(3), maackia- pterocarpan A(4),maackiapterocarpan B(5),Maackiaisoflavonoside(15), maackiachromone(39),(2S,3S)-7-methoxyflavononol(41),(-)-maackiacytisine(48);45 known compounds:abyssinone V(6),(—)-sigmoidin E(7),5-hydroxysophoranone(8), maackiaflavanone(9),abyssinone II(10),abyssinone IV(11),euchrenone b_1(12),ulexone B (13),ulexone A(14),Dalsympathetin(16),ononin(17),glycitin(18),genestin(19), Saikoisoflavonoside A(20),Afrormosin-7-O-β-D- glucopyranoside(21),gehuain(22), Kushenol O(23),7-hydroxy-4',6-dimethoxyisoflavone-7-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (24),tectoridin(25),biochanin A 7-O-β-D- gentiobioside(26),7-hydroxy4' -methoxyisoflavone-7-0-β-D-apiofuranosyl-(l→6)-β-.D-glucopy- ranoside(27),glycitin-6"-O-acetate (28),ononin-6"-O-acetate(29),7,5'-dihydroxy-3'-methoxyisoflavone(30), retusin-8-methylether(31),7,4'-dihydroxy-3'-methoxyisofiavone(32),di-O- methyldaidzein (33),genistein(34),afromosin(35),formononetin(36),prunetin(37),glycitein(38),(±)-2, 3-dihydro-3,5-dihydroxy-7- methoxyflavone(40),3,4-dimethoxy caffeic acid methylester (42),(-)-maackiain(43),(-)- medicarpin(44),ethyl P-hydroxylbenzoate(45),anisic acid(46), p-hydroxy benzaldehyde(47),cytisine(49),(±)-formylcytisine(50),N-(3- oxobutyl) cytisine (51),(-)-epibaptifoline(52).N-methylcytisine(53),β-sitosterol(54).Compounds 6,7.10-14, 16,21-24,26-28,30,31and 45-47 were firstly isolated from Maackia species,and compounds 8,32 were isolated from M.amurensis for the first time.
The cytotoxicities against human cancer cell lines(A375S2,HeLa,MCF-7 and HepG2) were tested by the MTT method in vitro,and all the tested compounds,including 4 new compounds:maackiaflavanone A(1),maackiaflavanone B(2),maackiaisoflavone(3), maackiaptecarpan A(4),demonstrated cytotoxic activities.Among the tested compounds, maackiaflavanone B(2) showed the strongest cytotoxic activity with IC_50 value of 7.8μM against A375S2 and euchrenone b_1(12) showed the most potent cytotoxicity with IC_50 value of 4.5μM against HeLa.The kinds of the tested compounds included prenylated flavonones, isoflavones and pterocarpans.
We also tested the cytochrome P450 enzyme inhibitory activities of 5-hydroxyl -sophoranone(8),(-)-maackiain(43),(-)-medicarpin(44) against CYP1A2、CYP2C9 and CYP3A4.All the three compounds showed inhibitory activities and(-)-medicarpin(44) showed strong inhibitory activity with IC-50 value of 10.7μM against CYP1A2.
For quality control of the stem bark of M.amurensis,the content of the total isofavonoids in the stem bark of M.amurensis were determined by UV Spectrophotometry .The HPLC fingerprint was studied on the bark of M.amurensis.Eighteen peaks in the HPLC fingerprint were identified by compared with the standard compounds,including 17 isoflavones.Additionally,the contents of four isoflavanes,genestin,tectoridin, Saikoisoflavonoside A and Maackiaisoflavonoside were determined.These standards will be useful for quality control of the medicinal material.
从朝鲜槐树皮70%的乙醇提取物中,经过多种色谱分离手段分离得到54个化合物,通过理化性质及波谱分析鉴定了这些化合物的结构,其中包括9个新化合物,分别命名为:怀槐二氢黄酮A(1,maackiaflavanone A),怀槐二氢黄酮B(2,maackiaflavanone B),怀槐异黄酮(3,maackiaisoflavone),怀槐紫檀烷A(4,maackiapterocarpan A),怀槐紫檀烷B(5,maackiapterocarpan B),怀槐异黄酮苷(15,Maackiaisoflavonoside),怀槐色原酮(39,maackiachromone),(2S,3S)-7-甲氧基二氢黄酮醇(41),(-)-怀槐金雀花碱(48,(-)-maackiacytisine);45个已知化合物:abyssinone V(6),(-)-sigmoidin E(7),5-hydroxysophoranone(8),maackiaflavanone(9),abyssinone II(10),abyssinone IV(11),euchrenone b_1(12),ulexone B(13),ulexone A(14),Dalsympathetin(16),芒柄花苷(17),鸡黄豆素苷(18),染料木苷(19),Saikoisoflavonoside A(20),阿夫罗摩辛-7-O-β-D-呲喃葡萄糖苷(21),gehuain(22),Kushenol O(23),4',6-二甲氧基-异黄酮-7-O-β-D-芹糖-(1→6)-β-D-吡喃葡萄糖苷(24),鸢尾种苷(25),5-羟基-4'-甲氧基-异黄酮-7-O-β-D-葡萄糖-(1→6)-β-D-吡喃葡萄糖苷(26),4'-甲氧基.异黄酮-7-O-β-D-芹糖-(1→6)-β-D-吡喃葡萄糖苷(27),glycitin-6"-O-acetate(28),ononin-6"-O-acetate(29),7,5'-dihydroxy-3'-methoxyisoflavone(30),retusin-8-methylether(31),7,4'-dihydroxy-3'-methoxyisoflavone(32),di-O-methyldaidzein(33),染料木素(genistein,34),阿夫罗摩辛(afromosin,35),芒柄花黄素(formononetin,36),樱黄素(prunetin,37),鸡黄豆素(glycitein,38),(±)-2,3-dihydro-3,5-dihydroxy-7-methoxyflavone(40),3,4-二甲氧基咖啡酸酯(42),高丽槐素(43)和美迪紫檀素(44),对羟基苯甲酸乙酯(45),对甲氧基苯甲酸(46),对羟基苯甲醛(47),金雀花碱(cytisine,49),(±)-formylcytisine(50),N-(3-oxobutyl)cytisine(51),(-)-epibaptifoline(52),N-methylcytisine(53)和β-谷甾醇(54)。其中化合物6,7,10—14,16,21—24,26-28,30,31,40,45—47等21个化合物为首次从马鞍树属植物中分离得到;化合物8,32为首次从朝鲜槐植物中分离得到。
根据朝鲜槐树皮民间抗肿瘤功效,选择一些特征性成分进行了细胞毒活性筛选。采用MTT法测试7个异戊烯基二氢黄酮(1,2,6-9,11),3个异戊烯基异黄酮(3,12,14);3个紫檀烷(4,43,44);及具有代表性的异黄酮染料木素(34),对人宫颈癌HeLa细胞、人黑色素瘤A375S2细胞、人乳腺癌MCF-7细胞和人肝癌HepG2细胞的细胞毒活性,结果所有被测试化合物均显示不同程度的细胞毒作用,其中怀槐二氢黄酮B抑制A375S2细胞IC_50值为7.8μM,euchrenone b_1抑制HeLa细胞IC_50值为4.5μM。
我们还首次对1个异戊烯基二氢黄酮5-hydroxysophoranone(8),及2个紫檀烷:高丽槐素(43)、美迪紫檀素(44)进行了细胞色素P450氧化酶CYPlA2、CYP2C9、CYP3A4抑制活性筛选研究,结果均显示较强的抑制活性,其中(一)-medicarpin(44)抑制CYPlA2IC_50值为10.7μM。
为了控制朝鲜槐药材的质量,首次采用紫外分光光度法测定朝鲜槐树皮中总黄酮含量约7.0%。对朝鲜槐树皮药材进行了HPLC指纹图谱研究,首次建立了朝鲜槐树皮药材HPLC指纹图谱方法,以分离得到的化学对照品,对朝鲜槐药材指纹图谱中23个特征峰进行了标定,共指认了18个色谱峰,其中17个为异黄酮类化合物,并采用HPLC法对2批朝鲜槐树皮药材中4个异黄酮苷:染料木苷、鸢尾种苷、Saikoisoflavonoside A及新化合物怀槐异黄酮苷进行了含量测定,为朝鲜槐及其相关制剂的质量控制研究奠定了基础。
Maackia amurensis Rupr.et Maxim.,belongs to the Leaguminosae family,Maackia species, is a deciduous tree distributed widely in the north of China.The dried stem bark of M. amurensis has been used as folk medicine for the treatment of rheumatoid arthritis,pain,allay inflammation,stanch bleeding,etc.In our country,little research on the chemical constituents and pharmacological activities of M.amurensis has been reported.For further development of this medicinal plant material,we conducted research on the chemical constituents,bioactivity and quality control of the stem bark of M.amurensis.
To study the chemical constituents of the M.amurensis,the constituents were isolated by various chromatography methods and the structures were elucidated on the basis of chemical and spectroscopic data.54 compounds were isolated from the 70%ethanol extract,including 9 new compounds:maackiaflavanone A(1),maackiaflavanone B(2),maackiaisoflavone(3), maackia- pterocarpan A(4),maackiapterocarpan B(5),Maackiaisoflavonoside(15), maackiachromone(39),(2S,3S)-7-methoxyflavononol(41),(-)-maackiacytisine(48);45 known compounds:abyssinone V(6),(—)-sigmoidin E(7),5-hydroxysophoranone(8), maackiaflavanone(9),abyssinone II(10),abyssinone IV(11),euchrenone b_1(12),ulexone B (13),ulexone A(14),Dalsympathetin(16),ononin(17),glycitin(18),genestin(19), Saikoisoflavonoside A(20),Afrormosin-7-O-β-D- glucopyranoside(21),gehuain(22), Kushenol O(23),7-hydroxy-4',6-dimethoxyisoflavone-7-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (24),tectoridin(25),biochanin A 7-O-β-D- gentiobioside(26),7-hydroxy4' -methoxyisoflavone-7-0-β-D-apiofuranosyl-(l→6)-β-.D-glucopy- ranoside(27),glycitin-6"-O-acetate (28),ononin-6"-O-acetate(29),7,5'-dihydroxy-3'-methoxyisoflavone(30), retusin-8-methylether(31),7,4'-dihydroxy-3'-methoxyisofiavone(32),di-O- methyldaidzein (33),genistein(34),afromosin(35),formononetin(36),prunetin(37),glycitein(38),(±)-2, 3-dihydro-3,5-dihydroxy-7- methoxyflavone(40),3,4-dimethoxy caffeic acid methylester (42),(-)-maackiain(43),(-)- medicarpin(44),ethyl P-hydroxylbenzoate(45),anisic acid(46), p-hydroxy benzaldehyde(47),cytisine(49),(±)-formylcytisine(50),N-(3- oxobutyl) cytisine (51),(-)-epibaptifoline(52).N-methylcytisine(53),β-sitosterol(54).Compounds 6,7.10-14, 16,21-24,26-28,30,31and 45-47 were firstly isolated from Maackia species,and compounds 8,32 were isolated from M.amurensis for the first time.
The cytotoxicities against human cancer cell lines(A375S2,HeLa,MCF-7 and HepG2) were tested by the MTT method in vitro,and all the tested compounds,including 4 new compounds:maackiaflavanone A(1),maackiaflavanone B(2),maackiaisoflavone(3), maackiaptecarpan A(4),demonstrated cytotoxic activities.Among the tested compounds, maackiaflavanone B(2) showed the strongest cytotoxic activity with IC_50 value of 7.8μM against A375S2 and euchrenone b_1(12) showed the most potent cytotoxicity with IC_50 value of 4.5μM against HeLa.The kinds of the tested compounds included prenylated flavonones, isoflavones and pterocarpans.
We also tested the cytochrome P450 enzyme inhibitory activities of 5-hydroxyl -sophoranone(8),(-)-maackiain(43),(-)-medicarpin(44) against CYP1A2、CYP2C9 and CYP3A4.All the three compounds showed inhibitory activities and(-)-medicarpin(44) showed strong inhibitory activity with IC-50 value of 10.7μM against CYP1A2.
For quality control of the stem bark of M.amurensis,the content of the total isofavonoids in the stem bark of M.amurensis were determined by UV Spectrophotometry .The HPLC fingerprint was studied on the bark of M.amurensis.Eighteen peaks in the HPLC fingerprint were identified by compared with the standard compounds,including 17 isoflavones.Additionally,the contents of four isoflavanes,genestin,tectoridin, Saikoisoflavonoside A and Maackiaisoflavonoside were determined.These standards will be useful for quality control of the medicinal material.
引文
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