Design,Synthesis And Biological Activity Of ?-carboline N-fused Imidazole Derivatives

?-carboline alkaloids are an important class of natural products with great potential for drug development.?-carboline alkaloids have a wide range of biological activities,including highly effective antibacterial,antitumor,antiviral,and antimalarial.Because of the superior biological activity of itself and its abundant derivatives,coupled with its relatively simple?-carboline parent ring structure,it has attracted widespread attention from researchers.Numerous scientific studies have shown that?-carboline alkaloids have prominent antitumor activities,but because of its poor cell selectivity,they have not been used clinically.Therefore,the development of antitumor drugs with novel structure,low toxic and side effects,and independent intellectual property rights has become a research hotspot for many scholars.Based on the previous research of our group,we take the?-carboline parent ring structure as the lead compound and combine the active structure-activity relationship of?-carboline alkaloids revealed in the previous stage to modified the structure and optimized the pharmacophore of?-carboline alkaloid.Furthermore,the structure of?-carboline alkaloid was modified to optimize the pharmacophore of?-carboline alkaloid.At the same time,the imidazo[1,2-a]pyridine structure,which also has excellent biological activity,is introduced into the?-carboline parent ring structure by applying the principle of active substructure medicinal effect splicing.Therefore,a series of new imidazole-substituted?-carboline alkaloid derivatives were designed and synthesized,and the antitumor activity of the obtained new compounds was evaluated in vitro.In order to obtain new compounds with high activity,it will lay a foundation for the development and clinical application of new anti-tumor drugs.In the first part,a total of 50 new?-carboimidazole derivatives were synthesized,by using L-tryptophan as the raw material,through Pictet-Spengler reaction,aromatization,alkylation,oxidation and other multi-step reactions,The imidazole ring structure was introduced in the 1-,2-position of 1-aldehyde-?-carboline substituted with different groups at 9-position.The products synthesized in this chapter are all new compounds,whose structures are confirmed by ¹H NMR,¹³C NMR and HRMS points,and the crystal structure of compound C5i'has been confirmed.Also,the compounds conducted a tumor cell line activity test.In the second part,the same method was used to modify the different active sites of?-carboline.We obtained 26 novel?-carboimidazole derivatives,which introduced the imidazole ring structure through the2-,3-position of 3-aldehyde-?-carboline substituted with different groups at the 9-position.Similarly,the compounds synthesized in this chapter have been confirmed to be new compounds by structure and tested for tumor cell line activity.A total of 76 novel target products were synthesized in this thesis.All compounds were tested for tumor cell line activity using the MTT method.The results show that most of the compounds have shown to A549?lung cancer cells?,BGC-823?gastric cancer cells?,CT-26?colon cancer cells?,Bel-7402?liver cancer cells?and MCF-7?breast cancer cells?excellent inhibitory activity.In summary,by introducing an imidazo[1,2-a]pyridine structure to the?-carboline alkaloid parent ring,a number of new?-carboimidazole derivatives with excellent antitumor activity have been obtained.Lay the foundation for the development and clinical application of new antitumor drugs.