兴安藜芦抗肿瘤活性成分的发现及结构修饰
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摘要
藜芦属(Veratrum Linn.)为百合科(Liliaceae)植物,据《中国植物志》记载我国有13个种和一个变种。中医用兴安藜芦(V. dahuricum)等四种藜芦属植物的根和根茎入药,用于中风痰壅,癫痫、喉痹不通,及疥癣和恶疮。藜芦属植物化学成分包括甾体生物碱类化合物、茋类化合物、二肽类、黄酮类及其它类化合物,其中生物碱是其主要活性成分。
1.兴安藜芦植物的化学成分研究
本课题中采用多种现代色谱手段系统分离了兴安藜芦根及根茎中的化学成分,从中得到60个单体化合物。并应用光谱学方法(1H-NMR, 13C-NMR, DEPT, 1H-1HCOSY, NOESY, HMQC, HMBC, ESI-MS, IR)鉴定其化学结构。分别为: XL-1:14α-羟基-?11-环杷明XL-2:Veratrobasine XL-3:环杷明XL-4:介芬胺XL-5:藜芦胺XL-6:藜芦托素XL-7:伪介芬胺XL-8:藜芦嗪XL-9:Veramitaline XL-10:Etioline XL-11:Etioline-3-O-glucoside XL-12:3-乙酰基-15-当归酰基计明碱XL-13:3, 7-二乙酰基-15-当归酰基计明碱XL-14:3-藜芦酰基计明碱XL-15:3-藜芦酰基-15-当归酰基计明碱XL-16:3-藜芦酰基-15-异戊酰基计明碱XL-17:3-乙酰基-15-异戊酰基计明碱XL-18:Germerine XL-19:15-当归酰基计明碱XL-20:3, 7-二当归酰基计明碱XL-21:3, 15-二当归酰基-7-乙酰基计明碱XL-22:3-当归酰计明碱XL-23:3-当归酰基棋盘花胺XL-24:3-藜芦酰基棋盘花胺XL-25:棋盘花胺XL-26:计明碱XL-27:白藜芦醇XL-28:2'-羟基白藜芦醇XL-29:(E)-白藜芦醇-3-O-葡萄糖苷XL-30:(Z)-白藜芦醇-3-O-葡萄糖苷XL-31:2'-羟基白藜芦醇-3-O-葡萄糖苷XL-32:白藜芦醇-4'-O-葡萄糖苷XL-33:2'-羟基白藜芦醇-4'-O-葡萄糖苷XL-34:4'-甲基白藜芦醇-3-O-葡萄糖苷XL-35:5-甲基白藜芦醇-3, 4'-O-二葡萄糖苷XL-36:2'-羟基白藜芦醇-3, 4'-O-二葡萄糖苷XL-37:异泽兰素XL-38:3', 4', 7-三甲基木犀草素XL-39:4'-甲基异鼠李素XL-40:木犀草素XL-41:山柰酚XL-42:槲皮素XL-43:芹菜素XL-44:4', 6-二甲氧基-5, 7-二羟基黄酮XL-45:金合欢素XL-46:槲皮素-7-O-鼠李糖苷XL-47:4', 5, 7-三羟基-6-甲氧基黄酮-7-O-葡萄糖苷XL-48:4'-羟基-3', 5-二甲基黄酮-7-O-葡萄糖苷XL-49:木犀草素-7-O-葡萄糖苷XL-50:金合欢素-7-O-葡萄糖苷XL-51:芹菜素-7-O-葡萄糖苷XL-52:槲皮素-3-O-葡萄糖苷XL-53:槲皮素-3-O-鼠李糖苷XL-54:蔗糖XL-55:β-谷甾醇XL-56:胡萝卜苷XL-57:苯甲酸XL-58:蜡醇XL-59:3, 4-二羟基苯甲酸XL-60:钩吻素子
其中,XL-1, 12, 13, 14, 15和35为新化合物;XL-2, 3, 9~11, 16~23, 25, 27~34, 36~54, 57~60为首次从兴安藜芦中分得。
2.兴安藜芦各提取部位和单体的药理活性研究
经过兴安藜芦总提取物、四个极性部位及总生物碱的急性毒性实验,发现藜芦的主要毒性成分为藜芦生物碱,主要存在于氯仿部位。兴安藜芦总提取物、总生物碱及单体化合物抑制肿瘤细胞增生的活性研究及体内抗肿瘤活性研究证明,藜芦中的藜芦胺和环杷明具有较强的肿瘤细胞毒活性,而环杷明则表现出良好的抗肿瘤活性,推测介芬胺类生物碱可能是藜芦抗肿瘤活性的物质基础。3.兴安藜芦药材的质量分析
建立了兴安藜芦HPLC-ELSD-MSn的质量控制方法,测定8批药材中6个主要有效成分的含量,结果显示各批次之间成分的含量相差很大。建立的检测方法可以方便的进行药材质量分析,便于控制质量,同时也确定了藜芦的最佳采收季节。
4.活性化合物的结构修饰
以藜芦胺,介芬胺和环杷明为底物,进行化学修饰,得到107个化合物,经过MTT法筛选出24个较先导化合物活性有明显增强的衍生物,选择其中3个化合物进行植入PANC-1肿瘤的小鼠的体内抗肿瘤活性研究,发现均有良好的体内抗肿瘤活性。
Veratrum dahuricum (Liliaceae) is one of the 14 species of the genus Veratrum in China. The rhizomes of some Veratrum species incuding Veratrum dahuricum, named as Lilu in Chinese traditional medicine, are used for some diseases such as aphasia arising apoplexy, epilepsy, wind type dysentery, jaundice, chronic malaria and acariasis. The crude extracts and compounds isolated from Veratrum plant havd benn reported possessing various pharmacological activities, including hypotensive, antithrombotic and antitumor function.
1. Chemical investigation of Veratrum dahuricum
By modern chromatographic methods, 60 compounds were isolated from the ethanol extract of rhizomes of Veratrum dahuricum. Their structures were elucidated on the basis of spectral data including 1H-NMR, 13C-NMR, DEPT, 1H-1HCOSY, NOESY, HMQC, HMBC, ESI-MS, IR, as follows: XL-1: 14α-hydroxy-?11-cyclopamine XL-2: Veratrobasine XL-3: Cyclopamine XL-4: Jervine XL-5: Veratramine XL-6: Veratrsine XL-7: Pseudojervine XL-8: Verazine XL-9: Veramitaline XL-10: Etioline XL-11: Etioline-3-O-glucoside XL-12: 3-acetyl-15-angyloylgermine XL-13: 3, 7-diacetyl-15-angeloylgermine XL-14: 3-veratroylgermine XL-15: 3-veratroyl-15angyloylgermine XL-16: 3-veratroyl-15-methylbutyrylgermine XL-17: 3-acetyl-15-methylbutyroylgermine XL-18: Germerine XL-19: 15-angyloylgermine XL-20: 3, 7-diangyloylgermine XL-21: 3, 15-diangyloyl-7-acetylgermine XL-22: 3-angeloylgermine XL-23: 3-angeloylzygadenine XL-24: 3-veratroylzygadenine XL-25: Zygadenine XL-26: Germine XL-27: Resveratrol XL-28: Oxyresveratrol XL-29: (E)-piceid XL-30: (Z)-piceid XL-31: Oxyresveratrol-3-O-glucoside XL-32: Resveratrol-4'-O-glucoside XL-33: Oxyresveratrol-4'-O-glucoside XL-34: 4'-methylresveratrol-3-O-glucoside XL-35: 2'-hydroxy-5-methylresveratrol-3, 4'- diglucosides XL-36: Mulberroside A XL-37: Eupatilin XL-38: 3', 4', 7-trimethylluteolin XL-39: 4'-methylisorhamnetin XL-40: Luteolin XL-41: Kaempferol XL-42: Quercetin XL-43: Apigenin XL-44: Pectolinaringenin XL-45: Acacetin XL-46: Quercetin-7-O-rhamnoside XL-47: 4', 5, 7-trihydroxy-6-methoxyl-7-O- glucoside XL-48: 4'-hydroxyl-3', 5-dimethoxylflavone-7-O -glucoside XL-49: Luteolin-7-O-glucoside XL-50: Acacetin-7-O-glucoside XL-51: Apigenin-7-O-glucoside XL-52: Quercetin-3-O-glucoside XL-53: Quercetin-3-O-rhamnoside XL-54: Sucrose XL-55:β-sitosterol XL-56:β-daucosterol XL-57: Benzoic acid XL-58: Cerylalcohol XL-59: 3, 4-dihydroxylbenzoic acid XL-60: Koumine
2. Pharmacology research on Veratrum dahuricum
The acute toxic trials showed that the total alkaloids extract was the most toxic of all the samples, including petroleum ether, CHCl3, EtOAC, n-BuOH fraction, ethanol extract and total alkaloids. The better cytotoxic and antitumor activities were found on the jerveratrum alkaloids compared to the ceveratrum alkaloids.
3. Determination of Six Steroidal Alkaloids of Veratrum dahuricum
A high performance liquid chromatography coupled with evaporative light scattering detection (HPLC-ELSD) and electrospray ionization multistage mass spectrometry (HPLC-ESI-MSn), respectively, has been performed for the simultaneous determination of six steroidal alkaloids, including pseudojervine, veratrosine, jervine, veratramine, 3-veratroylzygadenine, 3-angeloylzygadenine, in Veratrum dahuricum of different season. The plants were soaked in methanol and extracted ultrasonically. The intra-day and inter-day precisions of the method were evaluated and were less than 1.4%. The content of steroidal alkaloids in the plant varied significantly from spring to autumn, confirming the necessity to control the quality of Veratrum dahuricum during its preparation and application. And we know from this assay that the appropriate time for collecting the Veratrum dahuricum was from June 25 to July 10 for higher content of jervine.
4. The modification of three active compounds
We have gained above 107 derivatives of veratramine, jervine and cyclopamine by chemical and biotransformational methods. Among them, 24 compounds further optimized exhibited significent activities, thereinto, 3 compounds were tested in vivo assay, with promising antitumor activity. Especially, cyclopamine from Veratrum plant we studied, a special inhibitor to the Hedgehog signal pathway, had significant antitumor avtivity.
1.兴安藜芦植物的化学成分研究
本课题中采用多种现代色谱手段系统分离了兴安藜芦根及根茎中的化学成分,从中得到60个单体化合物。并应用光谱学方法(1H-NMR, 13C-NMR, DEPT, 1H-1HCOSY, NOESY, HMQC, HMBC, ESI-MS, IR)鉴定其化学结构。分别为: XL-1:14α-羟基-?11-环杷明XL-2:Veratrobasine XL-3:环杷明XL-4:介芬胺XL-5:藜芦胺XL-6:藜芦托素XL-7:伪介芬胺XL-8:藜芦嗪XL-9:Veramitaline XL-10:Etioline XL-11:Etioline-3-O-glucoside XL-12:3-乙酰基-15-当归酰基计明碱XL-13:3, 7-二乙酰基-15-当归酰基计明碱XL-14:3-藜芦酰基计明碱XL-15:3-藜芦酰基-15-当归酰基计明碱XL-16:3-藜芦酰基-15-异戊酰基计明碱XL-17:3-乙酰基-15-异戊酰基计明碱XL-18:Germerine XL-19:15-当归酰基计明碱XL-20:3, 7-二当归酰基计明碱XL-21:3, 15-二当归酰基-7-乙酰基计明碱XL-22:3-当归酰计明碱XL-23:3-当归酰基棋盘花胺XL-24:3-藜芦酰基棋盘花胺XL-25:棋盘花胺XL-26:计明碱XL-27:白藜芦醇XL-28:2'-羟基白藜芦醇XL-29:(E)-白藜芦醇-3-O-葡萄糖苷XL-30:(Z)-白藜芦醇-3-O-葡萄糖苷XL-31:2'-羟基白藜芦醇-3-O-葡萄糖苷XL-32:白藜芦醇-4'-O-葡萄糖苷XL-33:2'-羟基白藜芦醇-4'-O-葡萄糖苷XL-34:4'-甲基白藜芦醇-3-O-葡萄糖苷XL-35:5-甲基白藜芦醇-3, 4'-O-二葡萄糖苷XL-36:2'-羟基白藜芦醇-3, 4'-O-二葡萄糖苷XL-37:异泽兰素XL-38:3', 4', 7-三甲基木犀草素XL-39:4'-甲基异鼠李素XL-40:木犀草素XL-41:山柰酚XL-42:槲皮素XL-43:芹菜素XL-44:4', 6-二甲氧基-5, 7-二羟基黄酮XL-45:金合欢素XL-46:槲皮素-7-O-鼠李糖苷XL-47:4', 5, 7-三羟基-6-甲氧基黄酮-7-O-葡萄糖苷XL-48:4'-羟基-3', 5-二甲基黄酮-7-O-葡萄糖苷XL-49:木犀草素-7-O-葡萄糖苷XL-50:金合欢素-7-O-葡萄糖苷XL-51:芹菜素-7-O-葡萄糖苷XL-52:槲皮素-3-O-葡萄糖苷XL-53:槲皮素-3-O-鼠李糖苷XL-54:蔗糖XL-55:β-谷甾醇XL-56:胡萝卜苷XL-57:苯甲酸XL-58:蜡醇XL-59:3, 4-二羟基苯甲酸XL-60:钩吻素子
其中,XL-1, 12, 13, 14, 15和35为新化合物;XL-2, 3, 9~11, 16~23, 25, 27~34, 36~54, 57~60为首次从兴安藜芦中分得。
2.兴安藜芦各提取部位和单体的药理活性研究
经过兴安藜芦总提取物、四个极性部位及总生物碱的急性毒性实验,发现藜芦的主要毒性成分为藜芦生物碱,主要存在于氯仿部位。兴安藜芦总提取物、总生物碱及单体化合物抑制肿瘤细胞增生的活性研究及体内抗肿瘤活性研究证明,藜芦中的藜芦胺和环杷明具有较强的肿瘤细胞毒活性,而环杷明则表现出良好的抗肿瘤活性,推测介芬胺类生物碱可能是藜芦抗肿瘤活性的物质基础。3.兴安藜芦药材的质量分析
建立了兴安藜芦HPLC-ELSD-MSn的质量控制方法,测定8批药材中6个主要有效成分的含量,结果显示各批次之间成分的含量相差很大。建立的检测方法可以方便的进行药材质量分析,便于控制质量,同时也确定了藜芦的最佳采收季节。
4.活性化合物的结构修饰
以藜芦胺,介芬胺和环杷明为底物,进行化学修饰,得到107个化合物,经过MTT法筛选出24个较先导化合物活性有明显增强的衍生物,选择其中3个化合物进行植入PANC-1肿瘤的小鼠的体内抗肿瘤活性研究,发现均有良好的体内抗肿瘤活性。
Veratrum dahuricum (Liliaceae) is one of the 14 species of the genus Veratrum in China. The rhizomes of some Veratrum species incuding Veratrum dahuricum, named as Lilu in Chinese traditional medicine, are used for some diseases such as aphasia arising apoplexy, epilepsy, wind type dysentery, jaundice, chronic malaria and acariasis. The crude extracts and compounds isolated from Veratrum plant havd benn reported possessing various pharmacological activities, including hypotensive, antithrombotic and antitumor function.
1. Chemical investigation of Veratrum dahuricum
By modern chromatographic methods, 60 compounds were isolated from the ethanol extract of rhizomes of Veratrum dahuricum. Their structures were elucidated on the basis of spectral data including 1H-NMR, 13C-NMR, DEPT, 1H-1HCOSY, NOESY, HMQC, HMBC, ESI-MS, IR, as follows: XL-1: 14α-hydroxy-?11-cyclopamine XL-2: Veratrobasine XL-3: Cyclopamine XL-4: Jervine XL-5: Veratramine XL-6: Veratrsine XL-7: Pseudojervine XL-8: Verazine XL-9: Veramitaline XL-10: Etioline XL-11: Etioline-3-O-glucoside XL-12: 3-acetyl-15-angyloylgermine XL-13: 3, 7-diacetyl-15-angeloylgermine XL-14: 3-veratroylgermine XL-15: 3-veratroyl-15angyloylgermine XL-16: 3-veratroyl-15-methylbutyrylgermine XL-17: 3-acetyl-15-methylbutyroylgermine XL-18: Germerine XL-19: 15-angyloylgermine XL-20: 3, 7-diangyloylgermine XL-21: 3, 15-diangyloyl-7-acetylgermine XL-22: 3-angeloylgermine XL-23: 3-angeloylzygadenine XL-24: 3-veratroylzygadenine XL-25: Zygadenine XL-26: Germine XL-27: Resveratrol XL-28: Oxyresveratrol XL-29: (E)-piceid XL-30: (Z)-piceid XL-31: Oxyresveratrol-3-O-glucoside XL-32: Resveratrol-4'-O-glucoside XL-33: Oxyresveratrol-4'-O-glucoside XL-34: 4'-methylresveratrol-3-O-glucoside XL-35: 2'-hydroxy-5-methylresveratrol-3, 4'- diglucosides XL-36: Mulberroside A XL-37: Eupatilin XL-38: 3', 4', 7-trimethylluteolin XL-39: 4'-methylisorhamnetin XL-40: Luteolin XL-41: Kaempferol XL-42: Quercetin XL-43: Apigenin XL-44: Pectolinaringenin XL-45: Acacetin XL-46: Quercetin-7-O-rhamnoside XL-47: 4', 5, 7-trihydroxy-6-methoxyl-7-O- glucoside XL-48: 4'-hydroxyl-3', 5-dimethoxylflavone-7-O -glucoside XL-49: Luteolin-7-O-glucoside XL-50: Acacetin-7-O-glucoside XL-51: Apigenin-7-O-glucoside XL-52: Quercetin-3-O-glucoside XL-53: Quercetin-3-O-rhamnoside XL-54: Sucrose XL-55:β-sitosterol XL-56:β-daucosterol XL-57: Benzoic acid XL-58: Cerylalcohol XL-59: 3, 4-dihydroxylbenzoic acid XL-60: Koumine
2. Pharmacology research on Veratrum dahuricum
The acute toxic trials showed that the total alkaloids extract was the most toxic of all the samples, including petroleum ether, CHCl3, EtOAC, n-BuOH fraction, ethanol extract and total alkaloids. The better cytotoxic and antitumor activities were found on the jerveratrum alkaloids compared to the ceveratrum alkaloids.
3. Determination of Six Steroidal Alkaloids of Veratrum dahuricum
A high performance liquid chromatography coupled with evaporative light scattering detection (HPLC-ELSD) and electrospray ionization multistage mass spectrometry (HPLC-ESI-MSn), respectively, has been performed for the simultaneous determination of six steroidal alkaloids, including pseudojervine, veratrosine, jervine, veratramine, 3-veratroylzygadenine, 3-angeloylzygadenine, in Veratrum dahuricum of different season. The plants were soaked in methanol and extracted ultrasonically. The intra-day and inter-day precisions of the method were evaluated and were less than 1.4%. The content of steroidal alkaloids in the plant varied significantly from spring to autumn, confirming the necessity to control the quality of Veratrum dahuricum during its preparation and application. And we know from this assay that the appropriate time for collecting the Veratrum dahuricum was from June 25 to July 10 for higher content of jervine.
4. The modification of three active compounds
We have gained above 107 derivatives of veratramine, jervine and cyclopamine by chemical and biotransformational methods. Among them, 24 compounds further optimized exhibited significent activities, thereinto, 3 compounds were tested in vivo assay, with promising antitumor activity. Especially, cyclopamine from Veratrum plant we studied, a special inhibitor to the Hedgehog signal pathway, had significant antitumor avtivity.
引文
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