Study On Semi-synthesis Of Vica Alkaloids With Anti- Tumour Activities

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.