Design,Synthesis And Bioactivity Of Anticancer Paclitaxel-mimics

Paclitaxel,isolated from the stem bark of Taxus,has a very significant anticancer activity,and is known as the"plant gold".By accelerating tubulin assembly,paclitaxel inhibits the depolymerization of microtubules,blocks the G₂/M phase of cell cycle,and thereby results in apoptosis of tumor cell.Paclitaxel,along with its semi-synthetic derivatives docetaxel and cabazitaxel,have been successfully approved for market with in depth study of structural modification and structure-activity relationship.However,these drugs also have many defects,such as the scarcity of natural resources,difficulties in synthesis,poor water solubility,neurotoxicity in clinical use,neutropenia,and multidrug resistance,which limit their extensive use.In the mid-19th century,researchers,based on the structure of various compound molecules and their corresponding pharmacological effects,had the idea of putting them together in anticipation of using this method to synthesize new compounds with reduced toxicity and enhanced efficacy.However,due to the limitations of the experimental level at that time,there are few examples of the application of such compounds to clinical practice.With the development of experimental techniques and natural sciences,however,this idea has been accomplished in various chemical ways.For example,aspirin and acetaminophen,commonly used as antipyretic analgesics,researchers carry on the esterification of these two compounds to form benorylates,which not only eliminate the irritation to the stomach,but prolong the effect of the drug,thus enhancing the efficacy.Inspired by the above information,the thesis designed the following experiment:Replacing the complex four-ring system of paclitaxel diterpenes with the alkaloid compounds talasamin,songorine and steroid compounds DHEA,vitamin D₂,cholesterol,thus eight new paclitaxel mimics were obtained,and the structure of the new compounds was confirmed by ¹HNMR and ¹³CNMR.These novel paclitaxel mimics were screened by MTT method to test its inhibitory activity on human breast cancer cell MCF-7,human kidney clear cell adenocarcinoma cell 786-0,human colon cancer cell HCT-116 and non-small cell lung cancer A549,which demonstrated that DHEA-paclitaxel mimic showed significant inhibitory activity against human colon cancer cells HCT-116.Subsequently,the pharmacological activity of the drug was rescreened on the time and concentration dependence of the drug.The results presented that the inhibition rate of HCT-116 cell line decreased with decreasing concentration,and the drug activity was the strongest at 48 hours.Then this thesis,by studying the interpretations of apoptosis-related genes,explains the way drugs promote HCT116 cell apoptosis and therefore lays the foundation for the further exploration of the mechanism of pharmacological activity and the development of new anti-colon cancer drugs.