两类天然活性产物的转化与降解研究
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摘要
药用植物所含有效成分是防病治病的物质基础,研究发现药用有效成分进入体内会发生转化和代谢。本文选择与人体细胞色素P450有相似作用的雅致小克银汉霉AS3.2028对莪术醇和莪术二酮的微生物转化进行研究,以期发现新的活性转化产物；此外,丹酚酸B的衍生物已在临床作为注射液使用,但是其体内药物代谢还不清楚,在体外研究其稳定性和降解机制将对阐明其体内代谢提供理论支持。
一、研究雅致小克银汉霉(Cunninghamella elegans)AS3.2028对莪术醇和莪术二酮的环氧化催化,对雅致小克银汉霉AS3.2028的立体选择性催化和产物的HPLC行为进行研究。
雅致小克银汉霉AS3.2028转化莪术醇,从转化液中分离得到的一种主要转化产物,经波谱数据鉴定为七元环外碳碳双键被环氧化的产物,为10S,14-环氧莪术醇(10S,14-epoxycurcumol)。确立了10S,14-epoxycurcumol的HPLC-示差折光检测方法,绘制雅致小克银汉霉AS3.2028静息细胞转化曲线,研究底物和产物的量随时间的变化的动态过程,雅致小克银汉霉AS3.2028转化莪术醇在60小时莪术醇几乎全部被转化,产物具有非对映异构体立体选择性。
雅致小克银汉霉AS3.2028转化莪术二酮,转化产物经硅胶柱色谱分离得到两种主要转化产物,经波谱学鉴定为十碳环外碳碳双键发生环氧化,产物为(1S,10S)-1,10-环氧莪术二酮(1S,10S)-1,10-epoxycurdione和(1R,10R)-1,10-环氧莪术二酮(1R,10R)-1,10-epoxy-curdione。确立了产物HPLC-紫外检测方法,检测波长：285nm。考察了生长细胞转化莪术二酮的转化曲线,环氧化莪术二酮经过96小时的生物转化,只有76%的莪术二酮被转化成新的产物,但是产物的立体选择性不高。
选用细胞色素P450的经典诱导剂苯巴比妥、正十四烷和抑制剂胡椒基丁醚,1-氨基苯并三氮唑进行研究,初步确定了雅致小克银汉霉AS3.2028对莪术醇和莪二酮的转化是由雅致小克银汉霉AS3.2028细胞色素P450酶系参与完成。
依据CLSI(美国临床实验室标准化协会)的抗微生物药物敏感性试验操作方法和判断标准,研究了莪术醇和莪术二酮及其环氧化转化产物的体外抗真菌和抗细菌活性。结果表明莪术醇和莪术二酮对所试丝状真菌红色毛癣菌、疣状毛癣菌、石膏样小孢子菌、烟曲霉、黑根霉、黑曲霉均有抑菌活性,对酵母样真菌新型隐球菌、红色酵母菌亦有很好的抑菌效果,对典型革兰阳性菌金黄色葡萄球菌、枯草芽孢杆菌、枯草芽孢杆菌业种纳哆杆菌、藤黄八叠球菌和革兰阴性菌大肠埃希菌和产气肠杆菌无抑菌作用。
二、丹酚酸B粉末的影响因素试验表明：高温试验表明丹酚酸B在高温60℃下降解而在40℃没有明显降解,在室温高湿度试验中丹酚酸B吸收了大量的水,但在强光下没有明显的变化。丹酚酸B作为潜在的药物,应存放在室温下,并避免暴露在潮湿环境中。在固态下,包裹在铝箔袋中的丹酚酸B加速试验表明在加速条件下能够保持稳定6个月,在加速试验中相对稳定。溶于一般盐溶液的丹酚酸B的加速试验结果表明丹酚酸B的降解机制为一级降解,丹酚酸B在室温下T90为9天。显示丹酚酸B作为潜在药用物质能够以固体形态应用,但不适合以液态应用。
丹酚酸B降解产物经HPLC和ESI-TOFMS以负离子模式检测,检测出12种主要化合物,确认9个产物为丹酚酸B的降解产物,迷迭香酸和异丹酚酸确认为杂质。依据HPLC检测9种主要降解产物含量随热压处理时间变化结果,推断丹酚酸B可能的降解途径。
丹酚酸B获得一个质子生成丹酚酸E,当同时发生失去丹参素和二氧化碳时产生丹酚酸A,其后再经酯键的水解生成丹酚酸F。丹酚酸B也能够被水解释放丹参素从而生成紫草酸,其再经过失去原儿茶醛或丹参素后转化为丹酚酸D和原紫草酸。咖啡酸可能由原紫草酸通过苯并呋喃的开环作用和失去一分子咖啡酸而生成。此项丹酚酸B在溶液中稳定性的研究所得的结果为阐明丹酚酸B降解途径提供了更多的依据。
The effective constituents in the medical plants are the material basis for preventing and curing disease. Medical effective constituents can be converted and metabolized when getting inside the body. In this article Cunninghamella elegans AS3.2028which had similar effect with human cytochrome P450was chosen, in order to find new activated transformation products. Besides, the derivative of Sal B has already been used as injection fluid clinically, however, its drug metabolism in vivo is still unclear. The theoretical support for clarifying its metabolism in vivo will be provided by studying its stability and degradation mechanism in vitro.
First,Curcumol can be strongly transformed by Cunninghamella elegans AS3.2028. A major product was separated and purified from the biotransformation products, and it was identified as10S,14-epoxycurcumol, as epoxidation at the double bond outside the seven-memebered ring by spectroscopic analysis. The HPLC-analyzing method of10S,14-epoxycurcumol was established for the first time. Detector:differential refractometer detector. The transformation curve of Cunninghamella elegansAS3.2028resting cells was designed, and the status of the amount of substrate and product changing with time history and the dynamic process of stereoselectivity in biotransformation reaction were studied. Stereoselective epoxidation at the C10-C14double bond of curcumol can be catalyzed by C. elegans AS3.2028. After60h transformation almost all of curcumol has been converted, Cunninghamella elegans AS3.2028catalyze substrate shows the high stereoselectivity.
Curcumol can be converted by Cunninghamella elegans AS3.2028, meanwhile its isomer can also be effectively converted by Cunninghamella elegans AS3.2028. Curdione was converted96h for biotransformation by Cunninghamella elegans AS3.2028, and two main products were separated and purified through silica-gel column chromatography from the biotransformation products. It was identified that the epoxidation occurred at the C-C double bond outside the ten-memebered ring by using spectroscopic analysis, generating both (1S,10S)-1,10-epoxycurdione and (1R,10R)-1,10-epoxycurdione. The HPLC-UV analysis method was established. Detector wavelength:285nm. The biotransformation curve of curdione converted by growth cells was designed. After96h biotransformation for curdione, only76%percentage of curdione was converted into new products, however, the productivity of curdione epoxidation was not very high; some other products were also generated. The maximum concentration of (1S,10S)-1,10-epoxycurdione in biotransformation was determined to appear at96h, but the products stereoselectivity were not too high.
The high stereoselectivity for Cunninghamella elegans AS3.2028to catalyze substrate shows that it can be considerably utilized in chiral catalyzing. And it will have important significance to get further study. It was supposed that the cytochrome P450enzyme system in Cunninghamella elegans AS3.2028may catalyze the oxidation reaction. The cytochrome P450enzyme system in microorganism was widely used in bio-asymmetric synthesis epoxidation for a long time, so the classical inducers of cytochrome P450enzymes phenobarbital, n-tetradecane and the inhibitors piperonyl butoxide,1H-benzotriazol-1-amine were chosen and studied. It was identified that the cytochrome P450enzyme system participated the biotransformation of curcumol and curdione by Cunninghamella elegans AS3.2028.
According the standard and plans of Clinical and Laboratory Standards Institute (CLSI), the antibacterial and antifungal activity of curcumol, curdione and their epoxidation biotransformation products in vitro was studied for the first time. It was demonstrated from the results that both curcumol and curdione have well antimicrobial activity to molds in the test, and also have good antimicrobial activity to the yeast like fungi Cryptococcus neoformans and Rhodotorμla, and have no antimicrobial activity to the typical Gram-positive bacteria Staphyloccocus aureusm, Bacillus subtillis, Bacillus subtillis subsp.subtillis, Sarcina lutea and Gram-negative bacteria Escherichia coli and Enterobacter aerogenes.
Second,the test of influence factors of the Sal B powder shows that Sal B was reduced in the condition of60℃, while no remarkable decrease was observed at40℃. Under high temperature and high humidity conditions, Sal B powder absorbed a substantial amount of water, but no marked change was observed under the conditions of strong light. Sal B as a potential drμg material shoμld be stored at normal temperatures, and exposure to moisture shoμld be avoided. In the solid state, Sal B packaged in aluminum foil bags was stable for6months under "accelerated conditions", and Sal B powder was relatively stable during the accelerated testing. Accelerated testing resμlt of Sal B in NS solution indicates a first-order mechanism of decomposition. T90for Sal B was reached after9days'storage at room temperature, indicates that potential drμg material Sal B coμld be used in a solid formμlation, but it is not suitable for using as a liquid formμlation.
The degradation products of Sal B were identified throμgh HPLC analysis and ESI-TOFMS in negative mode. Twelve components were identified in the degraded sample of Sal B. Among them, nine components were identified as degradation products of Sal B. Rosmarinic acid and isosalvianolic acid B were determined to be impurities. HPLC was used to measure the changes with time of nine major degradation products content when they were treated in thermocompression condition, and according to the results, the possible pathway of degradation of Sal B was deduced. The pathway is feasible on the basis that Sal B has two ester bonds and one benzofuran, which are susceptible to decomposition. Sal B obtains a proton to generate Sal E, while the concurrent loss of DSU and carbon dioxide resμlts in the formation of Sal A, which then undergoes ester hydrolysis to Sal F. Sal B can also be hydrolyzed to release DSU to form Lit, which is converted into Sal D and Prolit after the loss of PRO or DSU. It is possible that Cafa is generated from Prolit via the ring-opening of benzofuran and the loss of one Cafa. The resμlts of stability testing of Sal B in solution provide more evidence towards elucidating the degradation pathway of Sal B.
一、研究雅致小克银汉霉(Cunninghamella elegans)AS3.2028对莪术醇和莪术二酮的环氧化催化,对雅致小克银汉霉AS3.2028的立体选择性催化和产物的HPLC行为进行研究。
雅致小克银汉霉AS3.2028转化莪术醇,从转化液中分离得到的一种主要转化产物,经波谱数据鉴定为七元环外碳碳双键被环氧化的产物,为10S,14-环氧莪术醇(10S,14-epoxycurcumol)。确立了10S,14-epoxycurcumol的HPLC-示差折光检测方法,绘制雅致小克银汉霉AS3.2028静息细胞转化曲线,研究底物和产物的量随时间的变化的动态过程,雅致小克银汉霉AS3.2028转化莪术醇在60小时莪术醇几乎全部被转化,产物具有非对映异构体立体选择性。
雅致小克银汉霉AS3.2028转化莪术二酮,转化产物经硅胶柱色谱分离得到两种主要转化产物,经波谱学鉴定为十碳环外碳碳双键发生环氧化,产物为(1S,10S)-1,10-环氧莪术二酮(1S,10S)-1,10-epoxycurdione和(1R,10R)-1,10-环氧莪术二酮(1R,10R)-1,10-epoxy-curdione。确立了产物HPLC-紫外检测方法,检测波长：285nm。考察了生长细胞转化莪术二酮的转化曲线,环氧化莪术二酮经过96小时的生物转化,只有76%的莪术二酮被转化成新的产物,但是产物的立体选择性不高。
选用细胞色素P450的经典诱导剂苯巴比妥、正十四烷和抑制剂胡椒基丁醚,1-氨基苯并三氮唑进行研究,初步确定了雅致小克银汉霉AS3.2028对莪术醇和莪二酮的转化是由雅致小克银汉霉AS3.2028细胞色素P450酶系参与完成。
依据CLSI(美国临床实验室标准化协会)的抗微生物药物敏感性试验操作方法和判断标准,研究了莪术醇和莪术二酮及其环氧化转化产物的体外抗真菌和抗细菌活性。结果表明莪术醇和莪术二酮对所试丝状真菌红色毛癣菌、疣状毛癣菌、石膏样小孢子菌、烟曲霉、黑根霉、黑曲霉均有抑菌活性,对酵母样真菌新型隐球菌、红色酵母菌亦有很好的抑菌效果,对典型革兰阳性菌金黄色葡萄球菌、枯草芽孢杆菌、枯草芽孢杆菌业种纳哆杆菌、藤黄八叠球菌和革兰阴性菌大肠埃希菌和产气肠杆菌无抑菌作用。
二、丹酚酸B粉末的影响因素试验表明：高温试验表明丹酚酸B在高温60℃下降解而在40℃没有明显降解,在室温高湿度试验中丹酚酸B吸收了大量的水,但在强光下没有明显的变化。丹酚酸B作为潜在的药物,应存放在室温下,并避免暴露在潮湿环境中。在固态下,包裹在铝箔袋中的丹酚酸B加速试验表明在加速条件下能够保持稳定6个月,在加速试验中相对稳定。溶于一般盐溶液的丹酚酸B的加速试验结果表明丹酚酸B的降解机制为一级降解,丹酚酸B在室温下T90为9天。显示丹酚酸B作为潜在药用物质能够以固体形态应用,但不适合以液态应用。
丹酚酸B降解产物经HPLC和ESI-TOFMS以负离子模式检测,检测出12种主要化合物,确认9个产物为丹酚酸B的降解产物,迷迭香酸和异丹酚酸确认为杂质。依据HPLC检测9种主要降解产物含量随热压处理时间变化结果,推断丹酚酸B可能的降解途径。
丹酚酸B获得一个质子生成丹酚酸E,当同时发生失去丹参素和二氧化碳时产生丹酚酸A,其后再经酯键的水解生成丹酚酸F。丹酚酸B也能够被水解释放丹参素从而生成紫草酸,其再经过失去原儿茶醛或丹参素后转化为丹酚酸D和原紫草酸。咖啡酸可能由原紫草酸通过苯并呋喃的开环作用和失去一分子咖啡酸而生成。此项丹酚酸B在溶液中稳定性的研究所得的结果为阐明丹酚酸B降解途径提供了更多的依据。
The effective constituents in the medical plants are the material basis for preventing and curing disease. Medical effective constituents can be converted and metabolized when getting inside the body. In this article Cunninghamella elegans AS3.2028which had similar effect with human cytochrome P450was chosen, in order to find new activated transformation products. Besides, the derivative of Sal B has already been used as injection fluid clinically, however, its drug metabolism in vivo is still unclear. The theoretical support for clarifying its metabolism in vivo will be provided by studying its stability and degradation mechanism in vitro.
First,Curcumol can be strongly transformed by Cunninghamella elegans AS3.2028. A major product was separated and purified from the biotransformation products, and it was identified as10S,14-epoxycurcumol, as epoxidation at the double bond outside the seven-memebered ring by spectroscopic analysis. The HPLC-analyzing method of10S,14-epoxycurcumol was established for the first time. Detector:differential refractometer detector. The transformation curve of Cunninghamella elegansAS3.2028resting cells was designed, and the status of the amount of substrate and product changing with time history and the dynamic process of stereoselectivity in biotransformation reaction were studied. Stereoselective epoxidation at the C10-C14double bond of curcumol can be catalyzed by C. elegans AS3.2028. After60h transformation almost all of curcumol has been converted, Cunninghamella elegans AS3.2028catalyze substrate shows the high stereoselectivity.
Curcumol can be converted by Cunninghamella elegans AS3.2028, meanwhile its isomer can also be effectively converted by Cunninghamella elegans AS3.2028. Curdione was converted96h for biotransformation by Cunninghamella elegans AS3.2028, and two main products were separated and purified through silica-gel column chromatography from the biotransformation products. It was identified that the epoxidation occurred at the C-C double bond outside the ten-memebered ring by using spectroscopic analysis, generating both (1S,10S)-1,10-epoxycurdione and (1R,10R)-1,10-epoxycurdione. The HPLC-UV analysis method was established. Detector wavelength:285nm. The biotransformation curve of curdione converted by growth cells was designed. After96h biotransformation for curdione, only76%percentage of curdione was converted into new products, however, the productivity of curdione epoxidation was not very high; some other products were also generated. The maximum concentration of (1S,10S)-1,10-epoxycurdione in biotransformation was determined to appear at96h, but the products stereoselectivity were not too high.
The high stereoselectivity for Cunninghamella elegans AS3.2028to catalyze substrate shows that it can be considerably utilized in chiral catalyzing. And it will have important significance to get further study. It was supposed that the cytochrome P450enzyme system in Cunninghamella elegans AS3.2028may catalyze the oxidation reaction. The cytochrome P450enzyme system in microorganism was widely used in bio-asymmetric synthesis epoxidation for a long time, so the classical inducers of cytochrome P450enzymes phenobarbital, n-tetradecane and the inhibitors piperonyl butoxide,1H-benzotriazol-1-amine were chosen and studied. It was identified that the cytochrome P450enzyme system participated the biotransformation of curcumol and curdione by Cunninghamella elegans AS3.2028.
According the standard and plans of Clinical and Laboratory Standards Institute (CLSI), the antibacterial and antifungal activity of curcumol, curdione and their epoxidation biotransformation products in vitro was studied for the first time. It was demonstrated from the results that both curcumol and curdione have well antimicrobial activity to molds in the test, and also have good antimicrobial activity to the yeast like fungi Cryptococcus neoformans and Rhodotorμla, and have no antimicrobial activity to the typical Gram-positive bacteria Staphyloccocus aureusm, Bacillus subtillis, Bacillus subtillis subsp.subtillis, Sarcina lutea and Gram-negative bacteria Escherichia coli and Enterobacter aerogenes.
Second,the test of influence factors of the Sal B powder shows that Sal B was reduced in the condition of60℃, while no remarkable decrease was observed at40℃. Under high temperature and high humidity conditions, Sal B powder absorbed a substantial amount of water, but no marked change was observed under the conditions of strong light. Sal B as a potential drμg material shoμld be stored at normal temperatures, and exposure to moisture shoμld be avoided. In the solid state, Sal B packaged in aluminum foil bags was stable for6months under "accelerated conditions", and Sal B powder was relatively stable during the accelerated testing. Accelerated testing resμlt of Sal B in NS solution indicates a first-order mechanism of decomposition. T90for Sal B was reached after9days'storage at room temperature, indicates that potential drμg material Sal B coμld be used in a solid formμlation, but it is not suitable for using as a liquid formμlation.
The degradation products of Sal B were identified throμgh HPLC analysis and ESI-TOFMS in negative mode. Twelve components were identified in the degraded sample of Sal B. Among them, nine components were identified as degradation products of Sal B. Rosmarinic acid and isosalvianolic acid B were determined to be impurities. HPLC was used to measure the changes with time of nine major degradation products content when they were treated in thermocompression condition, and according to the results, the possible pathway of degradation of Sal B was deduced. The pathway is feasible on the basis that Sal B has two ester bonds and one benzofuran, which are susceptible to decomposition. Sal B obtains a proton to generate Sal E, while the concurrent loss of DSU and carbon dioxide resμlts in the formation of Sal A, which then undergoes ester hydrolysis to Sal F. Sal B can also be hydrolyzed to release DSU to form Lit, which is converted into Sal D and Prolit after the loss of PRO or DSU. It is possible that Cafa is generated from Prolit via the ring-opening of benzofuran and the loss of one Cafa. The resμlts of stability testing of Sal B in solution provide more evidence towards elucidating the degradation pathway of Sal B.
引文
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