长春花属生物碱抗肿瘤药物的半合成研究
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摘要
长春花属生物碱(Vica Alkaloids)是从植物长春花Catharanthus roseus (L.) G.Don中提取得到或者在此基础上进行结构修饰得到的一类生物碱的总称,其中的多种活性结构具有很好的抗肿瘤活性,因而对长春花属生物碱进行高活性化合物的筛选以及在此基础上对其进行结构修饰以期得到活性更高、副作用更小的新的结构备受关注。长春瑞滨正是通过半合成得到的长春花属高效抗肿瘤药物的代表。
本论文首先建立了从长春碱合成长春瑞滨的合成及纯化工艺。长春碱在以乙醚为反应溶剂,CO2Cl2与DMF反应生成的复合物为脱水剂,底物浓度为20 mmol/L,25℃下反应得到脱水长春碱,收率为64.52±1.17%,高于文献报道的最大值55%。同时在该合成过程中,首次发现报道了6’-N_b-oxide-leurosine,3, 4-demthyl-leurosine,3- demthyo-leurosine等三种相关的副产物。脱水长春碱在经过溴代及缩环水解反应后,得到长春瑞滨,经过对溴代反应过程的单因素分析,得到了较好的工艺条件,长春瑞滨的收率为66.34±1.44%,与文献报道的最大值64%基本持平。并且,通过研究得到了硅胶干柱结合反向MCI-GEL CHP-20柱分离的新纯化方法,能够得到纯度大于98%的长春瑞滨,分离总收率达到80%,高于传统反复硅胶分离法的70%的收率。
其次,建立了基于生物信息学的长春花属生物碱抗肿瘤活性虚拟评价的新方法,并对合成过程中的副产物进行了活性评价,发掘其应用价值。研究发现,长春花属生物碱与紫杉醇具有同样的结合部位,都位于微管蛋白1jff的β亚基,该结合部位是一个类似于“凹陷”的区域。长春瑞滨及长春氟宁与1jff的结合“吻合度”最好,通过分子对接分析,将长春氟宁上的F原子用短C链的结构取代,或许会得到活性更好的小分子。6’-N_b-oxide-leurosine也表现出与微管蛋白具有较低的对接能,推测该化合物具有较高的抗肿瘤活性。并且根据其对接结构分析,将3位的-OCH3用C链较长的结构取代,将会得到比6’-N_b-oxide-leurosine活性更高的结构。
本论文还首次建立了从长春碱化学合成6’-N_b-oxide-leurosine的工艺,反应的总收率为67.61±2.11%。并且建立了该化合物合成长春瑞滨的方法,充分利用该途径能将从H2SO4-VBL合成VNR的合成总收率从44.79±1.58%提高到50.03±1.73%,远大于文献报道的最大值44.8%
再次,首次利用基于甘草细胞(Glycyrrhiza uralensis Fisch)的生物转化的方法得到了6’-N_b-oxide-leurosine。8.0 g的甘草细胞在250 ml液体培养条件下,最大能将26 mg的硫酸长春碱完全进行转化,转化率为84.5±2.01%,远高于化学合成的收率,为6’-N_b-oxide-leurosine的获取提供了全新的来源途径。
本文还分别利用混合实验设计、人工神经网络分析技术及响应面分析技术等先进的过程优化技术对长春瑞滨的合成过程进行了优化。得到了合成脱水长春碱的最佳工艺为:底物浓度为15 mmol/L,脱水剂用量与底物摩尔比为50,反应温度20℃,反应时间12 h,萃取剂乙醚与二氯甲烷的体积比10:1。在此条件下的实验收率为70.884±1.12%,比单因素分析后得到的结果64.52±1.17%有较大程度上的提高。最佳溴代反应工艺条件为:NBS用量为1.07 mol/mol(与底物当量比)、TFA用量为22 mL/L(每L反应体系加入的mL数)、反应温度为-68℃。在此工艺条件下,实际的反应收率为70.56±0.33%,高于优化前的66.34±1.44%。
利用最终优化好的条件,进行反应,将从硫酸长春碱合成长春瑞滨的合成总收率从44.79±1.58%提高到50.01±1.27%,高于文献报道的最大值44.8%,而若充分考虑6’-N_b-oxide-leurosine的补充途径,合成过程总收率将达到55.21±1.73%,大大高于文献报道的最大值。
最后,以小试工艺为基础,对以长春碱为原料合成长春瑞滨及其纯化过程进行了三个批次的放大。在分别投料20 g、25 g、30 g的三个批次实验中,从H2SO4-VBL合成VNR酒石酸盐,合成及纯化过程的总收率为36.35±0.10%,与小试工艺的44.16±1.38%基本持平,但远大于文献报道的最大值30.5%。
Vica Alkaloids including the alkaloids extract from Catharanthus roseus (L.) G.Don and its smi-synthetical alkaloids. Most of them have antitumour activities. The synthesis of derivatives (partial or total) and filtrated from Vica Alkaloids has been the subject of a considerable amount of work in the past years to find new structures with higher antitumour activities and lower side effects, such as vinorelbine.
Firstly, we established the methods of synthesize vinorelbine from vinblastine. Particular analysis has been done of many facors under the process of synthetize anhydrovinbastine from vinblastine sulfate. We found that the yield reaches 64.52±1.17% under the reaction conditions are: vinblastine is dissolved in aether and the concentration is 20 mmol/L; the reaction reagent is the reactant of CO2Cl2 and DMF; the reaction temperature is 25℃.This yield is higher than those reported before. And we identified serveal important by-products, which are first reported in the process of synthetize anhydrovinbastine. The most important structures are 6’-N_b-oxide-leurosine, 3-demthyo- leurosine and 3, 4- demthyl- leurosine.
We can obtain vinorelbine from anhydrovinblasitne through halogenation and hydroly- zation. After particular analysis of halogenation, the preferable reaction conditions were obtained and the yield reached 66.34±1.44%, as high as those reported before (64%). We can obtain 98% vinorelbine using twice column chromatography, silica gel dry-column and MCI-GEL CHP-20. The yield of purification reaches 80%, is higher than reported before (70%).
Secondly, we established the methods of filtrated the structures with high activities and how to synthesis its derivatives. Using virtual screen technology that bases on numerator docking, we found that Vica Alkaloids and taxol have the same integrate position with microtubule protein 1jff. Vinorelbine and vinoflunine are the wonderful structures integrate with this hollow area. The formed compounds are steady. Based on our research, we supposed that we can obtain higher antitumour activities structures when replaced F atom with some kind of short carbochain structures. 6’-N_b-oxide-leurosin also is a considerate sructure of integrate with the hollow area and a certain extent the formed compounds are steady. We supposed that 6’-N_b-oxide-leurosin also with high antitumour activities. Based on the structure analysis, we concluded that the antitumour activities would increase when replaced methoxy at 3 position with some kind of long carbochain structures.
And we firstly established the method to synthesize 6’-N_b-oxide-leurosin from vinblastine, the yield reaches 67.61±2.11%. And the method of synthesizes vinorelbine from 6’-N_b-oxide-leurosin also established.
Some researches were done in a bran-new field of biotransformation of vinblastine. We found that Glycyrrhiza uralensis Fisch can directional transform vinblastine to 6’-N_b- oxide-leurosine. The yield is higher than chemical method reaches 84.5±2.01% and 8.0 g plant cell can biotransformation 26 mg vinblastine. This is a bran-new route of obtained 6’-N_b-oxide-leurosine.
Process optimization has also been done by the new technologies, which are mixture design, ANN and RSM. Through these models we obtained the confirmed optimum reaction conditions: the concentration of vinblastine is 15 mmol/L; the stechiometric proportions between the dehydrate reagent and vinblastine is 50; the reaction temperature is 20℃and the duration is 12 hours; The extraction reagent after reaction is the mixture of aether and methylene chloride (V/V=10). The yield of anhydrovinblastine reaches 70.88%±1.12%, higher than before optimization (64.52±1.17%). And the yield of obtained vinborelbine from anhydrovinblastine reaches 70.56±0.33% after optimizatd by RSM, is also higher than before optimization (66.34±1.44%).
After the process optimization, the total yield reaches 50.01±1.27% from vinblastine sulfate to vinorelbine, is high than before reported (45%). The yield can increase to 55.21±1.73% when the 6’-N_b-oxide-leurosine route is considerate.
Finally, we magnified the mass of vinblastine sulfate to 20~30 g under the optimizated conditions. The amplificatory yield reaches 36.35±0.10% and lower than before magnification. But the yield is much higher than before reported (30.5%). The amplificatory results are satisfied.
本论文首先建立了从长春碱合成长春瑞滨的合成及纯化工艺。长春碱在以乙醚为反应溶剂,CO2Cl2与DMF反应生成的复合物为脱水剂,底物浓度为20 mmol/L,25℃下反应得到脱水长春碱,收率为64.52±1.17%,高于文献报道的最大值55%。同时在该合成过程中,首次发现报道了6’-N_b-oxide-leurosine,3, 4-demthyl-leurosine,3- demthyo-leurosine等三种相关的副产物。脱水长春碱在经过溴代及缩环水解反应后,得到长春瑞滨,经过对溴代反应过程的单因素分析,得到了较好的工艺条件,长春瑞滨的收率为66.34±1.44%,与文献报道的最大值64%基本持平。并且,通过研究得到了硅胶干柱结合反向MCI-GEL CHP-20柱分离的新纯化方法,能够得到纯度大于98%的长春瑞滨,分离总收率达到80%,高于传统反复硅胶分离法的70%的收率。
其次,建立了基于生物信息学的长春花属生物碱抗肿瘤活性虚拟评价的新方法,并对合成过程中的副产物进行了活性评价,发掘其应用价值。研究发现,长春花属生物碱与紫杉醇具有同样的结合部位,都位于微管蛋白1jff的β亚基,该结合部位是一个类似于“凹陷”的区域。长春瑞滨及长春氟宁与1jff的结合“吻合度”最好,通过分子对接分析,将长春氟宁上的F原子用短C链的结构取代,或许会得到活性更好的小分子。6’-N_b-oxide-leurosine也表现出与微管蛋白具有较低的对接能,推测该化合物具有较高的抗肿瘤活性。并且根据其对接结构分析,将3位的-OCH3用C链较长的结构取代,将会得到比6’-N_b-oxide-leurosine活性更高的结构。
本论文还首次建立了从长春碱化学合成6’-N_b-oxide-leurosine的工艺,反应的总收率为67.61±2.11%。并且建立了该化合物合成长春瑞滨的方法,充分利用该途径能将从H2SO4-VBL合成VNR的合成总收率从44.79±1.58%提高到50.03±1.73%,远大于文献报道的最大值44.8%
再次,首次利用基于甘草细胞(Glycyrrhiza uralensis Fisch)的生物转化的方法得到了6’-N_b-oxide-leurosine。8.0 g的甘草细胞在250 ml液体培养条件下,最大能将26 mg的硫酸长春碱完全进行转化,转化率为84.5±2.01%,远高于化学合成的收率,为6’-N_b-oxide-leurosine的获取提供了全新的来源途径。
本文还分别利用混合实验设计、人工神经网络分析技术及响应面分析技术等先进的过程优化技术对长春瑞滨的合成过程进行了优化。得到了合成脱水长春碱的最佳工艺为:底物浓度为15 mmol/L,脱水剂用量与底物摩尔比为50,反应温度20℃,反应时间12 h,萃取剂乙醚与二氯甲烷的体积比10:1。在此条件下的实验收率为70.884±1.12%,比单因素分析后得到的结果64.52±1.17%有较大程度上的提高。最佳溴代反应工艺条件为:NBS用量为1.07 mol/mol(与底物当量比)、TFA用量为22 mL/L(每L反应体系加入的mL数)、反应温度为-68℃。在此工艺条件下,实际的反应收率为70.56±0.33%,高于优化前的66.34±1.44%。
利用最终优化好的条件,进行反应,将从硫酸长春碱合成长春瑞滨的合成总收率从44.79±1.58%提高到50.01±1.27%,高于文献报道的最大值44.8%,而若充分考虑6’-N_b-oxide-leurosine的补充途径,合成过程总收率将达到55.21±1.73%,大大高于文献报道的最大值。
最后,以小试工艺为基础,对以长春碱为原料合成长春瑞滨及其纯化过程进行了三个批次的放大。在分别投料20 g、25 g、30 g的三个批次实验中,从H2SO4-VBL合成VNR酒石酸盐,合成及纯化过程的总收率为36.35±0.10%,与小试工艺的44.16±1.38%基本持平,但远大于文献报道的最大值30.5%。
Vica Alkaloids including the alkaloids extract from Catharanthus roseus (L.) G.Don and its smi-synthetical alkaloids. Most of them have antitumour activities. The synthesis of derivatives (partial or total) and filtrated from Vica Alkaloids has been the subject of a considerable amount of work in the past years to find new structures with higher antitumour activities and lower side effects, such as vinorelbine.
Firstly, we established the methods of synthesize vinorelbine from vinblastine. Particular analysis has been done of many facors under the process of synthetize anhydrovinbastine from vinblastine sulfate. We found that the yield reaches 64.52±1.17% under the reaction conditions are: vinblastine is dissolved in aether and the concentration is 20 mmol/L; the reaction reagent is the reactant of CO2Cl2 and DMF; the reaction temperature is 25℃.This yield is higher than those reported before. And we identified serveal important by-products, which are first reported in the process of synthetize anhydrovinbastine. The most important structures are 6’-N_b-oxide-leurosine, 3-demthyo- leurosine and 3, 4- demthyl- leurosine.
We can obtain vinorelbine from anhydrovinblasitne through halogenation and hydroly- zation. After particular analysis of halogenation, the preferable reaction conditions were obtained and the yield reached 66.34±1.44%, as high as those reported before (64%). We can obtain 98% vinorelbine using twice column chromatography, silica gel dry-column and MCI-GEL CHP-20. The yield of purification reaches 80%, is higher than reported before (70%).
Secondly, we established the methods of filtrated the structures with high activities and how to synthesis its derivatives. Using virtual screen technology that bases on numerator docking, we found that Vica Alkaloids and taxol have the same integrate position with microtubule protein 1jff. Vinorelbine and vinoflunine are the wonderful structures integrate with this hollow area. The formed compounds are steady. Based on our research, we supposed that we can obtain higher antitumour activities structures when replaced F atom with some kind of short carbochain structures. 6’-N_b-oxide-leurosin also is a considerate sructure of integrate with the hollow area and a certain extent the formed compounds are steady. We supposed that 6’-N_b-oxide-leurosin also with high antitumour activities. Based on the structure analysis, we concluded that the antitumour activities would increase when replaced methoxy at 3 position with some kind of long carbochain structures.
And we firstly established the method to synthesize 6’-N_b-oxide-leurosin from vinblastine, the yield reaches 67.61±2.11%. And the method of synthesizes vinorelbine from 6’-N_b-oxide-leurosin also established.
Some researches were done in a bran-new field of biotransformation of vinblastine. We found that Glycyrrhiza uralensis Fisch can directional transform vinblastine to 6’-N_b- oxide-leurosine. The yield is higher than chemical method reaches 84.5±2.01% and 8.0 g plant cell can biotransformation 26 mg vinblastine. This is a bran-new route of obtained 6’-N_b-oxide-leurosine.
Process optimization has also been done by the new technologies, which are mixture design, ANN and RSM. Through these models we obtained the confirmed optimum reaction conditions: the concentration of vinblastine is 15 mmol/L; the stechiometric proportions between the dehydrate reagent and vinblastine is 50; the reaction temperature is 20℃and the duration is 12 hours; The extraction reagent after reaction is the mixture of aether and methylene chloride (V/V=10). The yield of anhydrovinblastine reaches 70.88%±1.12%, higher than before optimization (64.52±1.17%). And the yield of obtained vinborelbine from anhydrovinblastine reaches 70.56±0.33% after optimizatd by RSM, is also higher than before optimization (66.34±1.44%).
After the process optimization, the total yield reaches 50.01±1.27% from vinblastine sulfate to vinorelbine, is high than before reported (45%). The yield can increase to 55.21±1.73% when the 6’-N_b-oxide-leurosine route is considerate.
Finally, we magnified the mass of vinblastine sulfate to 20~30 g under the optimizated conditions. The amplificatory yield reaches 36.35±0.10% and lower than before magnification. But the yield is much higher than before reported (30.5%). The amplificatory results are satisfied.
引文
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