Efficient Construction Of Carbazole And Pyrazole Derivatives And Their Antitumor Activity Research

Carbazole and pyrazole compounds are important heterocyclic compounds that widely exist in the fields of natural product chemistry and organic medicinal chemistry,and have long been used in many fields such as medicinal chemistry,material chemistry,and agrochemicals.How to realize the efficient construction and functional modification of such heterocyclic systems has always been a research hotspot of this type of compound,and the construction of natural alkaloid skeleton molecules with novel structures through multi-component reactions has the characteristics of simple operation and good atom economy.Based on this,this paper explores two multi-component reaction pathways for the efficient construction of multi-substituted carbazole and arylaminopyrazole derivatives,and then MTT（3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium）colorimetric method,the potential anti-tumor activity evaluation and structure-activity-relationship analysis of all the obtained compounds were carried out,in order to efficiently construct novel carbazole and pyrazole heterocyclic molecules The system provides new methods.The specific content of research is mainly in two parts:（1）Construction of carbazole derivatives by multi-component reaction and research on their antitumor activityUsing indole,Aldol-X bifunctional reagents and 1,3-dicarbonyl compounds as substrates,after screening and optimization of reaction conditions,the efficient construction of the multi-substituted carbazole skeleton was realized through a convenient three-component reaction.A series of multi-substituted carbazole derivatives with structural diversity were prepared by derivation design,mainly including three types of molecules:carbazole amide,carbazole hydrazide and carbazole hydrazone.The in vitro cytotoxic activity of all synthetic carbazole derivatives against 7901（gastric adenocarcinoma cells）,A875（human melanoma）and MARC145（African green monkey kidney cells）was evaluated.Preliminary results showed that compound 14a had high inhibitory activity against 7901 and A875 cancer cells,with the lowest IC₅₀of 11.8±1.26and 9.77±8.32μM,respectively,and could be used as a lead molecule for the development of new carbazole anticancer drugs.（2）Multi-component one-pot synthesis of pyrazole derivatives and their antitumor activityUsing hydrazine hydrate,substituted isothiocyanates,and 1,3-dicarbonyl compounds as starting materials,after screening the reaction conditions,Finally,with the simplest substrate,the three-component efficient construction of arylaminopyrazole heterocyclic skeleton molecules in the green solvent system was realized and the reaction mechanism was explored;this method has wide substrate adaptability,and provides a new method for the preparation of novel pyrazole derivatives new strategy.Subsequently,the application of the obtained polysubstituted pyrazole derivatives as potential anticancer drugs was investigated,among which 18ea,18ec,18h,18s and 18z have been shown to be effective against A875（human melanoma）and Hep G2（liver cancer cell）cells The line has excellent anticancer activity,and the possible structure-activity relationship is discussed based on the screening results.Kinase assay and molecular docking experiments indicated that this compound may be a potential CDK1 inhibitor.