Synthesis And Antitumor Activity Of N-N-bridged β-carboline Derivatives

Cancer is one of the leading causes of death in the world,and natural products have been the main source of drugs to treat various diseases.β-carboline alkaloids are an important heterocyclic natural products with good pharmacological activities,such as antidepressant,anticonvulsant,anticonvulsant,antitumor,etc.,and are good medicinal potential.Isatin（indole-2,3-dione）is widely found in natural compounds,and its derivatives can act on various biological targets.Many anticancer drugs have isatin structure,indicating that isatin is an effective structural unit for the development of new anticancer drugs.Thiazole rings have been found to be an integral part of therapeutic structures and are widely used.Therefore,the design and synthesis of novel and low cytotoxicβ-carboline antitumor drugs containing cytophosphorin and thiazole has become a focus of attention.Based on the previous work of the research group,this thesis mainly uses the existing active structure-activity relationship to modify theβ-carboline ring,and uses the principle of active substructure pharmacodynamic concatenation,through nucleophilic addition-condensation reaction to connectβ-carboline with isatin and thiazole derivatives,to obtain a series of novel structureβ-carboline derivatives.It is hoped that through exploration and research,the syntheticβ-carboline derivatives will make a breakthrough in the treatment of cancer,and provide useful reference for the design and anticancer mechanism of new anticancer drugs.In the first part,using L-tryptophan as raw material,through Pictet-Spengler reaction,esterification,oxidation,N⁹-alkylation and reduction,important intermediates of 3-aldehyde-β-carboline derivatives are obtained,and further introduction of isatin unit.Thus,a series ofβ-carboline derivatives containing different substituents at 1-,9-and 3-were generated,and total synthesis of 24 compounds.The resulting compounds are new compounds,all structure by melting point,¹H NMR,¹³C NMR and HRMS confirmed.The antitumor activity of all compounds was tested and molecular docking calculation was performed.In the second part,important intermediates of 3-aldehyde-β-carboline derivatives were synthesized by the same method as in the first part.Further,thiazole units were introduced by reacting with thiourea and2-Bromoacetophenone containing different substituents,so as to obtain a series of 3-site thiazol-introducingβ-carboline derivatives,and a total of 33 compounds were synthesized.Similarly,33 compounds were confirmed to be novel compounds,and the antitumor activity was tested and the molecular docking calculation was performed.In this study,a total of 57 target compounds were synthesized.The antitumor activity of five tumor cell strains A549,BGC-823,CT-26,Bel-7402 and MCF-7 in vitro was evaluated by MTT assay.It was found that most of the compounds had moderate to good activity on the tested cells but had inhibitory selectivity,and some compounds had excellent antitumor activity,even higher than the positive control（cisplatin）.For example,compounds Y7m’and Y7q’synthesized in Chapter 2 and compounds Z2l and Z2n synthesized in Chapter 3 showed broad-spectrum antitumor activity on 5 types of tested cells.In addition,the results of molecular docking calculation showed that the target compound was well bound to the target protein,which side verified that the compound had good antitumor activity.In conclusion,in this study,by introducing isatin and thiazole pharmacodynamic structures into theβ-carboline alkaloid ring through N-N bridging,multipleβ-carboline derivatives with excellent antitumor activity were obtained,which enriched the database of antitumor compounds and laid a foundation for future drug development and clinical application.