Structural Modifications And Anti-tumor Activity Of Carthamine

Cichorium endivia.L,a kind of traditional Chinese medicine produced in Henan,Hunan,Sichuan,Xinjiang and Tibet and other places,has the functions of promoting blood circulation,removing blood stasis,removing dampness and swelling.It is reported that more than 200 chemical components of different structural types,with a variety of biological activities,have been separated from it.widely used in Chinese medicine treatment.Among them,carthamine B,an important extract,is a tetrahydro-?-carboline alkaloid with anti-tumor activity.This thesis focuses on the extract of Chinese medicinal materials Cichorium endivia.L-Carthamine B.The research screened its targets and indications in reverse,and found that based on Carthamine B and optimizing its structure,the designed compound can effectively bind to the estrogen receptor ER?.Therefore,through computer-aided drug design,classical medicinal chemistry research methods and structure-activity relationship analysis,this project designed and synthesized a series of selective estrogen receptor inhibitors(SERDs),and carried out anti-tumor activity studies in vivo and in vitro.In addition,based on the research and using PROTAC technology,the design,synthesis and anti-tumor activity of PROTAC molecules targeting ERa were carried out.The main research work is summarized as follows:1.Carthamine B was used as the matrix to optimize the structure,design and synthesize 5 series of 87 target compounds with different structures.2.The designed and synthesized target compounds were studied for their binding force to ER protein,ER degradation level and inhibitory activity on MCF-7 cells.Among them,D series and E series compounds showed better in vitro activity.3.For compounds better in vitro activity,pharmacokinetic studies including mouse metabolic stability,tissue distribution,CYP inhibition,hERG,plasma protein binding rate,liver microsomal stability and so on were conducted to further screen for target compounds with druggability.And the compounds D4,and E12 were found that in vivo pharmacokinetics are better than the positive drugs,and have lower toxicity.The in vivo exposure of compound E12 reached more than 10 times that of the positive control.4.For the compound E12 with the best in vitro activity and pharmacokinetic data,further studies on the pharmacodynamics in mice were carried out.In the MCF-7 subcutaneous xenograft inhibition experiment on nude mice,the anti-tumor efficacy of the compound E12 at a low dose of 0.6 mg or high doses of 2 mg/kg was significantly better than that of the positive control AZD9496 under the same dose.5.In addition,this project used PROTAC technology to conduct preliminary anti-breast cancer researches on target compounds with better activity.A total of 12 target compounds were designed and synthesized,and anti-tumor activity studies were carried out.F8 showed better anti-tumor activity.6.A total of 99 target compounds were synthesized,none of which has been reported in the literature,and one compound has the value of further study.In summary,using Carthamine B as the research object,this project adopts computer science technology,Hot-spot-based drug molecular design methods and traditional medicinal chemistry research methods,and the design,synthesis and biological activity researches of SERDs targeting ERa have been studied for breast cancer indications.A number of compounds with good activity both in vivo and in vitro have been obtained,laying a certain foundation for the following in-depth research.