Efficient Synthesis And Antitumor Activity Study Of Evodiamine And Its Derivatives

Traditional Chinese medicine is one of the important sources of modern drug discovery.Many natural active molecules have been isolated from traditional Chinese medicine.Fructus evodiae is a traditional Chinese medicine,and it is recorded in Shennong Materia Medica,which is the earliest Chinese medicine literature.For its major role in the recipe,Fructus evodiae has the functions of dispelling cold,relieving pain,reducing vomiting,helping Yang,and stopping diarrhea.Natural product scientists have isolated more than 100 compounds from Fructus evodiae,among which Evodiamine(EVO),one of the indole alkaloids,has been proven to have various biological activities.The anti-inflammatory,antibacterial,anti-Alzheimer’s,anti-obesity and antitumor effects of EVO were reviewed in this thesis.EVO has a broad-spectrum antitumor activity,which can inhibit proliferation,induce apoptosis,and arrest the cell cycle of a variety of common tumor cells.In addition,EVO has been reported to have targeted inhibition of topoisomerase(Topo)and tubulin.However,EVO’s tumor treatment ability is insufficient to go to clinical.As a result,it is necessary to optimize the structure of EVO to improve its antitumor activity.Some progress has been made in such work,including the atom substitution of different positions on the EVO skeleton and the splicing of other different active molecules with EVO.The structure-activity relationship and splicing strategies of EVO derivatives were summarized and it was found that modifications on position 14 of EVO had certain antitumor effects,but previous studies were not comprehensive.Therefore,60 14-position phenyl substituted EVO derivatives were synthesized in one step with triethyl protoformate as the key carbon source and Lewis acid as the catalyst to enrich the molecular library of evodiamine derivatives in this thesis.Subsequently,the antitumor structure-activity relationships of these derivatives were summarized,and three lead compounds with good antitumor activities were obtained.Among them,compound 8 could exert anti-HCC effect by inhibiting Topo Ⅰ and achieved a certain effect in vivo;compound 6f has a good anti-gastrointestinal tumor activity in vitro;compound 4b might target both Topo Ⅰ and tubulin to exert anti-gastrointestinal tumor effect.In conclusion,the three lead molecules validated by a series of experiments in vitro and in vivo and might provide new directions for drug development for the treatment of hepatocellular tumors and gastrointestinal tumors.