Design,Synthesis And Activity Of Imidazopyrido[3,4-b] Indole Derivatives

β-carboline alkaloids are a large group of natural and synthetic indole alkaloids,some of which are widely distributed in nature,including various plants,foods,marine organisms,insects,mammals and human tissues and body fluids.β-carboline alkaloids have important pharmacological and therapeutic properties,including sedative,anxiolytic,hypnotic,anticonvulsant,antitumour,antiviral,antiparasitic,antibacterial and other activities.It is of particular interest to pharmacologists and chemists because of its anti-tumour activity.In view of the increased demand,research is being carried out to exploit their structural diversity,biological and pharmacological activities,reduce their potential risks and develop new drugs in order to develop moreβ-carboline derivatives with excellent pharmacological activities.Therefore,a series of novelβ-carboline and imidazole ring derivatives were synthesized by structural modification ofβ-carboline alkaloids and the introduction of an imidazole ring at the 1,2-position through the active splicing principle.Chapter 2:Synthesis of intermediate compounds with different substituents at the 1-position and 9-position by Pictet-Spengler reaction,aromatization,alkylation and reduction,followed by reaction with amino acids with different substituents,resulting in the synthesis of a series ofβ-carboline derivatives with an imidazole ring introduced at the 1-position.The structures of the compounds synthesised in this chapter were confirmed by ¹H NMR,¹³C NMR and HRMS,and single crystal structure confirmation was done for one of the compounds 5q,and compounds were tested for activity in tumour cell lines.Chapter 3 content:As the range of reactions was limited by the small number of amino acid species present in the Chapter 1 content,a method with a wider range of reactions was wanted.In the later stage,a one-pot synthesis of the target compound was achieved using the intermediate compound1-methyl-β-carboline derivative with different substituents at the nine positions synthesised in Chapter 2,with cuprous iodide and copper acetate monohydrate as catalysts,di-tert-butyl peroxide as oxidant and dimethyl sulfoxide as solvent,simplifying the reaction process and increasing the The range of substrates was extended.The structures of the compounds synthesised in this chapter have been confirmed by ¹H NMR,¹³C NMR and HRMS,and compounds have been tested for activity in tumour cell lines.In this thesis,62β-carbolinobenzimidazole derivatives at the 1,2-position were synthesized and some of the compounds were tested for their anti-tumour activity against five tumour cell lines,namely 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）,using the MTT method.The results showed that most of the compounds exhibited excellent inhibitory activity against all five tumour cell lines.In addition,we performed molecular docking studies on the more active compounds and found good docking with the VEGFR2 active site.In summary,a total of 62 target compounds were obtained by introducing imidazole structures at the1,2-positions of the parent ring ofβ-carboline alkaloids through the active substructure splicing principle in this thesis.The in vitro antitumor activity tests revealed that several compounds showed excellent antitumor activity,and they have good prospects for subsequent antitumor drug development and clinical applications.