乌头碱型生物碱的模拟炮制研究
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摘要
有毒中药对于疑难杂症常有独特疗效,炮制后可减毒存效用于临床,这是中医用药的特色之一。阐明有毒中药炮制机理是规范炮制工艺、提高饮片质量标准、减少临床不良反应的核心和难点问题,也是有毒中药饮片能否从经验范畴走向科学化和现代化的关键。中药发挥作用的药效成分复杂,在炮制过程中发生成分的水解、分解、结合、络合等反应,而且非主要药效毒性成分也会与药效毒性成分之间发生反应或者影响其反应的过程,通过单体成分或成分群在模拟饮片的炮制条件下炮制,可以将复杂问题简单化,研究简单环境下的反应规律后,逐步扩展到饮片的整体炮制,明确炮制过程中成分变化途径及其规律,为从分子水平阐明饮片炮制机理提供实验依据。中药模拟炮制是指将中药饮片中的主要药效、毒性成分或组分,模拟饮片的炮制条件进行炮制,研究炮制前后的成分变化,结合药理毒理实验研究,为阐明饮片炮制的科学内涵提供依据。附子、川乌、草乌等乌头属有毒中药临床应用广泛,其成分-毒理-药理研究较清楚,但炮制减毒存效机理尚不十分明确。通过毒效成分乌头碱型生物碱的模拟炮制研究,结合量子化学计算的方法和高效液相色谱-质谱联用等现代分析技术,能够更加清楚的证明炮制过程中的成分变化,为中药炮制机理研究提供新的思路和方法。
本文分析了双酯型生物碱乌头碱、次乌头碱等在不同模拟炮制条件下的反应产物,结合量子化学计算预测和验证未知产物结构,推测反应机理和计算反应的历程,通过分析附子饮片在炮制过程的成分变化规律,明确实验和理论计算模拟炮制与饮片炮制过程中成分变化的相关性,深入分析阐释炮制减毒存效机理。主要研究内容有以下三个方面：
1在不同溶剂中的模拟炮制研究
比较乌头碱在水中加热不同时间的HPLC色谱图,发现：通过水解、分解等反应,乌头碱含量降低,且生成多种产物,各种产物的含量随时间变化规律不一致。苯甲酰乌头原碱是主要产物,但是与乌头碱的含量变化趋势并不呈正相关关系,炮制的过程中存在成分的相互转化和反应平衡,随着时间的延长,产物数量逐渐减少。采用液质联用技术确定了3种水解和分解产物的结构。次乌头碱在水中分解速度较乌头碱明显变慢,苯甲酰次乌头原碱是主要产物,但是二者的变化趋势并不呈比例关系,苯甲酰次乌头原碱随时间延长增加速度较慢,而次乌头碱的减少速度较快,在加热过程中反应不断发生,苯甲酰次乌头原碱生成速度和分解速度有差异,呈现逐渐增加再降低的趋势。质谱分析发现了次乌头碱、焦次乌头碱、次乌头原碱和脱水次乌头原碱等4种水解或分解产物。
比较乌头碱在稀乙醇中加热不同时间与在水中加热不同时间的HPLC色谱图,发现：乌头碱在稀乙醇中分解速度和在水中类似,在加热过程中分解较快,生成多种产物,在炮制的过程中存在反应平衡。质谱研究鉴定了5种反应产物,其中8-乙氧基-14-苯甲酰基乌头原碱和8-乙酰基-14-乙氧基乌头原碱两种醇解产物为乌头碱与乙醇反应的特征产物。中乌头碱在稀乙醇中加热不同时间与乌头碱有类似的反应发生,加入乙醇使加热后的产物更加复杂。质谱鉴定了5种成分,其中8-乙氧基-14-苯甲酰基中乌头原碱和8-乙酰基-14-乙氧基中乌头原碱两种醇解产物为中乌头碱与乙醇反应的特征产物。这些醇解产物的发现为附子、川乌等有毒中药加酒炮制或制备药酒的研究提供了指标成分。
比较乌头碱在甲醇中加热不同时间的HPLC色谱图,可见乌头碱加热后产生了新成分,经过液质联用分析发现在甲醇中通过加热主要发生醇解反应,生成8-甲氧基-14-苯甲酰基乌头原碱,这是乌头碱与甲醇反应的特征产物。次乌头碱在甲醇和水加热样品中检测到8-甲氧基-14-苯甲酰基次乌头原碱和8-甲氧基次乌头原碱两种醇解产物。这些醇解产物的发现为川乌等乌头属有毒中药在化学成分及含量测定的研究中,分析溶剂的选择及其对主要成分变化的影响提供了依据。
2附子饮片炮制前后化学成分的比较研究
为验证模拟炮制的变化在实际中药饮片炮制中是否存在,制备附子的生品和制品,采用液质联用的方法,分析了附子炮制前后成分的变化,对比生附片和制附片的成分组成,有22个成分为生、制附片共有,生附片具有的9个成分在制品中没有检测到,制附片中有17个成分是炮制后新产生的。根据附子、川乌、草乌等乌头属中药中所含乌头碱类成分的结构特点,及炮制过程中的成分水解或分解规律,预测了炮制后可能产生的成分结构及质谱信息。
3模拟炮制产物的量子化学计算研究
在初步根据质谱信息推测了产物结构的基础上,结合单体模拟炮制的结果和量子化学计算,进一步确定反应产物结构和反应历程。通过比较不同基组计算结果,确定了采用DFT/B3LYP/6-31G(d)的量子化学计算方法。采用高斯和Materials Studio两种方法,计算了焦乌头碱的结构,结果表明焦乌头碱应是C15羰基式结构,与已有文献报道一致。又采用高斯计算推测了焦中乌头碱、焦次乌头碱和脱水乌头原碱的结构。采用Materials Studio软件中的Dmol3模块,函数设置采用GGA和BLYP,计算了乌头碱二步水解的反应历程,找到了中间体和过渡态,得到了反应能垒。
综上所述,本文采用高效液相色谱法和质谱法检测了双酯型生物碱在水、稀乙醇、甲醇等不同溶剂中的反应产物,分析了不同产物的结构和变化规律,找到了多种与乙醇、甲醇反应生成的新特征产物,对比了附子炮制前后的成分变化,证实炮制产生了多种成分,采用量子化学计算的方法进一步确定了模拟炮制产物的结构,计算了乌头碱的二步水解反应历程,为深入阐明乌头属中药的炮制机理提供了依据,可指导乌头类有毒中药的炮制工艺优化和质量标准提高。本文将实验和理论计算两种方法相结合并相互验证,成分模拟炮制与饮片炮制相结合进行验证,为中药炮制机理研究提供了思路和方法。
Toxic drugs often have a unique effect on incurable diseases, and are used after process, which functions in decreasing toxicity and increasing efficacy, in clinic. This phenomenon is the clinical characteristics of TCM. To clarify the processing mechanism of toxic Chinese medicine is not only the key and difficult problems in specifying processing technology, improving quality standards and reducing clinical adverse reactions, but also will be the key step of TCM to transit from the experience to science. Chinese medicine often plays a role in the efficacy of their complex compositions. During processing, the ingredients endure concocting hydrolysis, decomposition, reaction, and the non-reaction or response process take place between the main toxic ingredients, and which are of efficacy and pharmaco-dynamics of toxic components. Through monomer ingredient or constituent group of the processing conditions of the simulation pieces process, we can simplify complex issues to study the law of reaction in a simple environment, and gradually extend to the pieces of a whole processed, clearly processed up the process of composition variation, clarity pieces processing mechanism to provide a basis. Chinese medicine simulation process in the efficacy of TCM, toxic components, or components, simulation piece process condition, processing, composition changes before and after processing of the study, the combination of pharmacology and toxicology experiments provide the basis for the study, to clarify the mechanism of pieces process. Monkshood and Aconitum were widely used in clinical application of toxic drugs. Their composition-toxicology-pharmacology are more clearly studied, but decreasing toxicity and increasing efficacy of process is unclear. It can be stated more clearly using quantum chemistry calculation methods combined with high performance liquid chromatography-mass spectrometry and other modern analytical techniques changes in the process of TCM process. This paper tried to provide new ideas and methods.
This paper analyzed the diester alkaloids in the different simulation process under the conditions of the reaction products, predicted and verified the unknown structure of the product using quantum chemical calculations, and suggested the course of the reaction mechanism and the calculation of reaction, the composition variation through the analysis of raw aconite pieces in the process of concocting clear experimental and theoretical computer simulation. There were in-depth analysis to explain the decreasing toxicity and increasing efficacy. The main contents are as follows:
1 A simulation process study in different solvents
Several different reaction products were found during aconitine heated in water at different times of chromatography, by hydrolysis, decomposition reaction, aconitine to produce a variety of products. And product content is inconsistent with the laws of time. The benzoyl aconitum is the main product, but the trend of aconitine is not in correlates with the reaction equilibrium, and with time, the product gradually reduced. LC-MS identified three kinds of hydrolysis and the structure of the decomposition products. Obvious of the decomposition rate hypaconitine aconitine in water is obviously slower than aconitine. The benzoyl hypaconitine is the main product, but two trends are not proportional to the benzoyl aconitine extended over time to increase slower, faster, and reduce the speed of hypaconitine reactions continue to occur during the heating process, benzoyl Aconitum original alkali to generate speed and there are differences in decomposition rate, showing a gradual deceleration increase in the trend of lower.4 compounds were identified using mass spectrometry.
Heating at different times of aconitine in dilute ethanol and heated in water at different times of the chromatograms, and found that aconitine in dilute ethanol decomposition rate and similar in water, decomposed faster in the heating process to produce a variety of product, concocted the reaction equilibrium. Using mass spectrometry, five kinds of reaction products were identified, among them,8-ethoxy-14-benzoylmesaconine and 8-acetyl-14-ethoxymesaconine are the alcoholysis products of aconitine ethanol response characteristics of the product. Aconitine in dilute ethanol, heated at different times and aconitine have a similar reaction, ethanol is added to the heating of the product is more complex. Mass spectrometry identified five kinds of ingredients,8-ethoxy-14-benzoyl aconitine original base and 8-acetyl-14-ethoxy Aconitum two original alkali alcohol solution product of aconitine ethanol response characteristics of the product. Alcoholysis products found for monkshood, Aconitum Aconitum is toxic drugs and liquor concocted or preparation of tincture of the index components.
Aconitine is heated in methanol at different times, and HPLC shows that the aconitine heated ingredients, after the LC-MS analysis showed that by heating occurs mainly in methanol alcoholysis reaction to generate 8-methoxy-14-benzoylaconice, is the aconitine reaction of methanol and the characteristics of the product. Hypaconitine detected in samples of methanol and water heating to the 8-methoxy-14-benzoyl hypaconine and two kinds of alcohol-methoxy-hypaconitine original alkali decomposition products. The discovery of these glycolysis products Aconitum genus Aconitum and other toxic drugs provided a basis for the choice of solvent in the determination of research.
2 Composition change before and after process
To verify the simulation results, aconite sample before and after process were analyzed using LC-MS, there are 22 ingredients in the raw and processed pieces. During the process, 17 components were produced and 9 compounds were dispeared. According to the Aconitum structural characteristics of traditional Chinese medicine contained in the composition of Aconitum, monkshood, processed ingredients in the process of hydrolysis or decomposition of the law, that may ingredients after the processed ingredients and MS were predicted.
3 Quantum chemical calculations of processed product
Based on the structure identified by mass spectra and results of based on the results of simulation process, as well as quantum chemical calculations, reaction product structure and the reaction course were confirmed. To compare different basis sets DFT/B3LYP/6-31G (d) was identified. Gaussian calculations and Materials Studio are two ways to calculate the structure. The results show it is dehydrated aconitine. It is the same with paper reported in the literature, at the same time, dehydrated aconitine, dehydrated mesaconitine and dehydrated hypaconitine were calculated. Using Materials Studio software Dmo13 module, the GGA and BLYP were set, aconitine two-step hydrolysis reaction course was calculated, the intermediates and transition states and the reaction barrier were found.
In summary, the reaction product of diester alkaloids were detected in water, dilute ethanol and methanol solvent using high performance liquid chromatography and mass spectrometry. The new features of the product generated by reaction were found by analysis the ethanol structure and variation of different products, to find a number of, methanol, compared to composition changes before and after processing of the aconite, processed up a variety of ingredients, using the method of quantum chemical calculations to further define the analog processed product structure, calculated aconitine of two-step hydrolysis reaction course, provide a basis for elucidating Aconitum Chinese medicine processing mechanism that can guide the toxic drugs of the Aconitum concocted process optimization and quality standards to improve. In this paper, the ideas and methods for the process mechanism of Chinese medicine was provided using experiment and theoretical calculation, simulation process and pieces process.
本文分析了双酯型生物碱乌头碱、次乌头碱等在不同模拟炮制条件下的反应产物,结合量子化学计算预测和验证未知产物结构,推测反应机理和计算反应的历程,通过分析附子饮片在炮制过程的成分变化规律,明确实验和理论计算模拟炮制与饮片炮制过程中成分变化的相关性,深入分析阐释炮制减毒存效机理。主要研究内容有以下三个方面：
1在不同溶剂中的模拟炮制研究
比较乌头碱在水中加热不同时间的HPLC色谱图,发现：通过水解、分解等反应,乌头碱含量降低,且生成多种产物,各种产物的含量随时间变化规律不一致。苯甲酰乌头原碱是主要产物,但是与乌头碱的含量变化趋势并不呈正相关关系,炮制的过程中存在成分的相互转化和反应平衡,随着时间的延长,产物数量逐渐减少。采用液质联用技术确定了3种水解和分解产物的结构。次乌头碱在水中分解速度较乌头碱明显变慢,苯甲酰次乌头原碱是主要产物,但是二者的变化趋势并不呈比例关系,苯甲酰次乌头原碱随时间延长增加速度较慢,而次乌头碱的减少速度较快,在加热过程中反应不断发生,苯甲酰次乌头原碱生成速度和分解速度有差异,呈现逐渐增加再降低的趋势。质谱分析发现了次乌头碱、焦次乌头碱、次乌头原碱和脱水次乌头原碱等4种水解或分解产物。
比较乌头碱在稀乙醇中加热不同时间与在水中加热不同时间的HPLC色谱图,发现：乌头碱在稀乙醇中分解速度和在水中类似,在加热过程中分解较快,生成多种产物,在炮制的过程中存在反应平衡。质谱研究鉴定了5种反应产物,其中8-乙氧基-14-苯甲酰基乌头原碱和8-乙酰基-14-乙氧基乌头原碱两种醇解产物为乌头碱与乙醇反应的特征产物。中乌头碱在稀乙醇中加热不同时间与乌头碱有类似的反应发生,加入乙醇使加热后的产物更加复杂。质谱鉴定了5种成分,其中8-乙氧基-14-苯甲酰基中乌头原碱和8-乙酰基-14-乙氧基中乌头原碱两种醇解产物为中乌头碱与乙醇反应的特征产物。这些醇解产物的发现为附子、川乌等有毒中药加酒炮制或制备药酒的研究提供了指标成分。
比较乌头碱在甲醇中加热不同时间的HPLC色谱图,可见乌头碱加热后产生了新成分,经过液质联用分析发现在甲醇中通过加热主要发生醇解反应,生成8-甲氧基-14-苯甲酰基乌头原碱,这是乌头碱与甲醇反应的特征产物。次乌头碱在甲醇和水加热样品中检测到8-甲氧基-14-苯甲酰基次乌头原碱和8-甲氧基次乌头原碱两种醇解产物。这些醇解产物的发现为川乌等乌头属有毒中药在化学成分及含量测定的研究中,分析溶剂的选择及其对主要成分变化的影响提供了依据。
2附子饮片炮制前后化学成分的比较研究
为验证模拟炮制的变化在实际中药饮片炮制中是否存在,制备附子的生品和制品,采用液质联用的方法,分析了附子炮制前后成分的变化,对比生附片和制附片的成分组成,有22个成分为生、制附片共有,生附片具有的9个成分在制品中没有检测到,制附片中有17个成分是炮制后新产生的。根据附子、川乌、草乌等乌头属中药中所含乌头碱类成分的结构特点,及炮制过程中的成分水解或分解规律,预测了炮制后可能产生的成分结构及质谱信息。
3模拟炮制产物的量子化学计算研究
在初步根据质谱信息推测了产物结构的基础上,结合单体模拟炮制的结果和量子化学计算,进一步确定反应产物结构和反应历程。通过比较不同基组计算结果,确定了采用DFT/B3LYP/6-31G(d)的量子化学计算方法。采用高斯和Materials Studio两种方法,计算了焦乌头碱的结构,结果表明焦乌头碱应是C15羰基式结构,与已有文献报道一致。又采用高斯计算推测了焦中乌头碱、焦次乌头碱和脱水乌头原碱的结构。采用Materials Studio软件中的Dmol3模块,函数设置采用GGA和BLYP,计算了乌头碱二步水解的反应历程,找到了中间体和过渡态,得到了反应能垒。
综上所述,本文采用高效液相色谱法和质谱法检测了双酯型生物碱在水、稀乙醇、甲醇等不同溶剂中的反应产物,分析了不同产物的结构和变化规律,找到了多种与乙醇、甲醇反应生成的新特征产物,对比了附子炮制前后的成分变化,证实炮制产生了多种成分,采用量子化学计算的方法进一步确定了模拟炮制产物的结构,计算了乌头碱的二步水解反应历程,为深入阐明乌头属中药的炮制机理提供了依据,可指导乌头类有毒中药的炮制工艺优化和质量标准提高。本文将实验和理论计算两种方法相结合并相互验证,成分模拟炮制与饮片炮制相结合进行验证,为中药炮制机理研究提供了思路和方法。
Toxic drugs often have a unique effect on incurable diseases, and are used after process, which functions in decreasing toxicity and increasing efficacy, in clinic. This phenomenon is the clinical characteristics of TCM. To clarify the processing mechanism of toxic Chinese medicine is not only the key and difficult problems in specifying processing technology, improving quality standards and reducing clinical adverse reactions, but also will be the key step of TCM to transit from the experience to science. Chinese medicine often plays a role in the efficacy of their complex compositions. During processing, the ingredients endure concocting hydrolysis, decomposition, reaction, and the non-reaction or response process take place between the main toxic ingredients, and which are of efficacy and pharmaco-dynamics of toxic components. Through monomer ingredient or constituent group of the processing conditions of the simulation pieces process, we can simplify complex issues to study the law of reaction in a simple environment, and gradually extend to the pieces of a whole processed, clearly processed up the process of composition variation, clarity pieces processing mechanism to provide a basis. Chinese medicine simulation process in the efficacy of TCM, toxic components, or components, simulation piece process condition, processing, composition changes before and after processing of the study, the combination of pharmacology and toxicology experiments provide the basis for the study, to clarify the mechanism of pieces process. Monkshood and Aconitum were widely used in clinical application of toxic drugs. Their composition-toxicology-pharmacology are more clearly studied, but decreasing toxicity and increasing efficacy of process is unclear. It can be stated more clearly using quantum chemistry calculation methods combined with high performance liquid chromatography-mass spectrometry and other modern analytical techniques changes in the process of TCM process. This paper tried to provide new ideas and methods.
This paper analyzed the diester alkaloids in the different simulation process under the conditions of the reaction products, predicted and verified the unknown structure of the product using quantum chemical calculations, and suggested the course of the reaction mechanism and the calculation of reaction, the composition variation through the analysis of raw aconite pieces in the process of concocting clear experimental and theoretical computer simulation. There were in-depth analysis to explain the decreasing toxicity and increasing efficacy. The main contents are as follows:
1 A simulation process study in different solvents
Several different reaction products were found during aconitine heated in water at different times of chromatography, by hydrolysis, decomposition reaction, aconitine to produce a variety of products. And product content is inconsistent with the laws of time. The benzoyl aconitum is the main product, but the trend of aconitine is not in correlates with the reaction equilibrium, and with time, the product gradually reduced. LC-MS identified three kinds of hydrolysis and the structure of the decomposition products. Obvious of the decomposition rate hypaconitine aconitine in water is obviously slower than aconitine. The benzoyl hypaconitine is the main product, but two trends are not proportional to the benzoyl aconitine extended over time to increase slower, faster, and reduce the speed of hypaconitine reactions continue to occur during the heating process, benzoyl Aconitum original alkali to generate speed and there are differences in decomposition rate, showing a gradual deceleration increase in the trend of lower.4 compounds were identified using mass spectrometry.
Heating at different times of aconitine in dilute ethanol and heated in water at different times of the chromatograms, and found that aconitine in dilute ethanol decomposition rate and similar in water, decomposed faster in the heating process to produce a variety of product, concocted the reaction equilibrium. Using mass spectrometry, five kinds of reaction products were identified, among them,8-ethoxy-14-benzoylmesaconine and 8-acetyl-14-ethoxymesaconine are the alcoholysis products of aconitine ethanol response characteristics of the product. Aconitine in dilute ethanol, heated at different times and aconitine have a similar reaction, ethanol is added to the heating of the product is more complex. Mass spectrometry identified five kinds of ingredients,8-ethoxy-14-benzoyl aconitine original base and 8-acetyl-14-ethoxy Aconitum two original alkali alcohol solution product of aconitine ethanol response characteristics of the product. Alcoholysis products found for monkshood, Aconitum Aconitum is toxic drugs and liquor concocted or preparation of tincture of the index components.
Aconitine is heated in methanol at different times, and HPLC shows that the aconitine heated ingredients, after the LC-MS analysis showed that by heating occurs mainly in methanol alcoholysis reaction to generate 8-methoxy-14-benzoylaconice, is the aconitine reaction of methanol and the characteristics of the product. Hypaconitine detected in samples of methanol and water heating to the 8-methoxy-14-benzoyl hypaconine and two kinds of alcohol-methoxy-hypaconitine original alkali decomposition products. The discovery of these glycolysis products Aconitum genus Aconitum and other toxic drugs provided a basis for the choice of solvent in the determination of research.
2 Composition change before and after process
To verify the simulation results, aconite sample before and after process were analyzed using LC-MS, there are 22 ingredients in the raw and processed pieces. During the process, 17 components were produced and 9 compounds were dispeared. According to the Aconitum structural characteristics of traditional Chinese medicine contained in the composition of Aconitum, monkshood, processed ingredients in the process of hydrolysis or decomposition of the law, that may ingredients after the processed ingredients and MS were predicted.
3 Quantum chemical calculations of processed product
Based on the structure identified by mass spectra and results of based on the results of simulation process, as well as quantum chemical calculations, reaction product structure and the reaction course were confirmed. To compare different basis sets DFT/B3LYP/6-31G (d) was identified. Gaussian calculations and Materials Studio are two ways to calculate the structure. The results show it is dehydrated aconitine. It is the same with paper reported in the literature, at the same time, dehydrated aconitine, dehydrated mesaconitine and dehydrated hypaconitine were calculated. Using Materials Studio software Dmo13 module, the GGA and BLYP were set, aconitine two-step hydrolysis reaction course was calculated, the intermediates and transition states and the reaction barrier were found.
In summary, the reaction product of diester alkaloids were detected in water, dilute ethanol and methanol solvent using high performance liquid chromatography and mass spectrometry. The new features of the product generated by reaction were found by analysis the ethanol structure and variation of different products, to find a number of, methanol, compared to composition changes before and after processing of the aconite, processed up a variety of ingredients, using the method of quantum chemical calculations to further define the analog processed product structure, calculated aconitine of two-step hydrolysis reaction course, provide a basis for elucidating Aconitum Chinese medicine processing mechanism that can guide the toxic drugs of the Aconitum concocted process optimization and quality standards to improve. In this paper, the ideas and methods for the process mechanism of Chinese medicine was provided using experiment and theoretical calculation, simulation process and pieces process.
引文
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