Design,Synthesis And Anticancer Activity Evaluation Of Three Different Types Of Natural Product Derivatives

Cancer is one of the most serious diseases threatening human health,has become a worldwide problem.As cancer is a kind of highly heterogeneous disease,it is easy to cause drug resistance and differences in treatment sensitivity,and the existing treatment methods often fail to achieve the desired therapeutic effect.Thus,exploring new anticancer drugs is urgent.Natural products refer to organic compounds separated and extracted from organisms that exist in nature,which is an important source of new chemical entity drugs.In this thesis,starting from three different sources of natural products,three different types of novel natural product derivatives were designed and synthesized,followed by a systematic anticancer activity study,with a view to discovering lead compounds with better anticancer activity.The contents mainly include the following three parts:1.Starting from the natural product Honokiol,combining with the structural features of current MTAs,forty novel honokiol derivatives(HoAns)were designed and synthesized using functional group fusion strategies.First,based on the results of in vitro antiproliferative activity and structure-activity relationship analysis,the optimal derivative HoAn32 was determined.Subsequently,the target and binding sites of HoAn32 were confirmed,and the effects on the cycle distribution,apoptosis induction and ROS production of tumor cells were evaluated.In addition,the in vitro antiangiogenic activity and the in vivo anti-SW620 xenograft effect as well as toxicity of nude mice of HoAn32 were also investigated in detail.2.Starting from the natural product coumarin,combining with an important functional group fragment-dithiocarbamate,twenty novel coumarin derivatives(IDs)were designed and synthesized using functional group splicing strategy.Based on the in vitro antiproliferative activity results of these derivatives on three different CRC cell lines and NCM460 cells,the optimal derivative ID-11 was determined.Subsequently,the potential target of ID-11 was confirmed,and its effect on cell cycle distribution,apoptosis induction and the expression of downstream genes was investigated in different CRC cells.In addition,the physicochemical properties and ADMET characteristics of ID-11 were also predicted.3.Starting from the natural product cyanidin and to improve the stability of its structure,forty cyanidin derivatives(HPs)with more stable structures were designed and synthesized by adopting the principle of bioisosterism.Based on the in vitro antiproliferative activity results of these derivatives on two different breast cancer cell lines,the optimal derivative HP37 was determined.Subsequently,the effects of HP37 on the cycle distribution,apoptosis induction,ROS production and cell migration of breast cancer cells were investigated.Finally,the anti-breast cancer effect of HP37 in vivo was also evaluated.