The Synthesis And Antitumor Evaluation Of Multi-region Modified 1-Deoxypaclitaxel Analogues

Taxol,a natural drug first isolated from the back of the Taxus brevfolia,is one of the most important antitumor agents.Taxol has become the top-priority drug for cancers,also known as the last line of defense terminal cancer owing to its special anticancer mechanism and broad-spectrum antitumor activity.However,the natural content of paclitaxel is so low that it is far from meeting the needs of clinical medicine and basic scientific research.In addition,paclitaxel has some drawbacks such as poor solubility,multiple drug resistence?MDR?and lacking the selectivity between the tumor cells and normal tissue.The study of structure-activity relationship shows that functional groups on the backbone are extremely important for the anticancer activity of paclitaxel,and the changes of functional groups cause changes in water solubility and anticancer activity.Therefore,while striving to expand paclitaxel resources,researchers are also looking for paclitaxel analogs that are more abundant in source,better water solubility,and have comparable or higher anticancer activity than paclitaxel.1-Deoxybaccatin VI,which is extracted from roots of Taxus chinensis in relatively high yield and reserves the essential pharmacophore,proves to be the valuable starting material for research.It is great significance to develop new paclitaxel analogues base on 1-deoxybacctin VI,not only to ease up the supplying cries of paclitaxel but also to thoroughly make use of the natural resourses.The whole thesis consists of the following parts:Firstly,in purpose of improving the antitumor activities of paclitaxel analogues and blocking the metabolic inactivation,the novel 1-deoxybaccatin VI derivatives modified with carbonate group at C-7,C-9 positions and C-9,C-10 positions are synthesized from 1-deoxybacctin VI.In the process of synthesis,we find that the introduction of carbonate group at different position has large influences on reaction activity of 1-deoxybaccatin VI derivatives.The C-7,C-9 and C-10 modified intermediate compounds are obtained by exploring of synthetic routes and optimizing of reaction conditions.This method is easy,efficient.And it lays the foundation for the synthesis of multi-region modified 1-deoxypaclitaxel analogues.Secondly,oxazolidine side chain precursor and?-lactam side chains precursor which could enhance biological activity of paclitaxel analogues are prepared from simple structure materials.Then,sixteen new paclitaxel analogues are obtained by coupling the side chains intermediates with novel C-7,C-9 and C-10 positions modified 1-deoxybaccatin VI derivatives under optimized condition.All structures of these conpounds are characterized by ¹H NMR,¹³C NMR,¹⁹F NMR and HR-MS.This method is efficient and practical,moreover,it expand the semi-synthesis routes of paclitaxel analogues.The antitumor activity study in vitro of 1-deoxypaclitaxel analogues indicates that part of compounds show comparable or slight improved biological activity when against A549 cell lines,and most compounds show better biological activity when against A549/T cell lines.Thirdly,Molecular stacking method was used to study the difference between the crystal structures of compounds 112b,taxol and taxotere and further explain the reason why the activity of compound 112b is better than paclitaxel.