Design,Synthesis And Antitumor Activity Of 6-(C-C/C-N)-β-Carboline Derivatives

According to the statistics of the World Health Organization,cancer is still one of the major factors hindering the improvement of life expectancy in China and the world in recent years.At present,chemotherapy is one of the main measures to treat cancer,but there are some problems,such as large by-effects and unsatisfactory efficacy of drugs,especially the emergence of multi-drug resistant tumor cell lines aggravates the difficulty of cancer treatment,and it is urgent to develop new anti-tumor drugs.β-carboline alkaloids have a wide range of biological activities.It is considered as a good drug skeleton.A variety of naturalβ-carboline alkaloids have good antitumor activities.Due to the diversity ofβ-carboline modification sites,a variety of excellent antitumor molecules can be obtained through structural modification ofβ-carboline.In recent reports,the modification ofβ-carboline rings mainly focuses on C¹,N²,C³,and N⁹-position,while there are few reports on C⁵,C⁶,C⁷,and C⁸.Recently,C⁶,C⁷,and C⁸substitutedβ-carboline have been reported to be cytotoxic.In the previous stage,we introduced N-aryl substituents into the C⁶-position ofβ-carboline and obtained molecules with strong antitumor activity.On this basis,we propose to introduce substituted aryl group and cyclic imidearyl group into the C⁶position ofβ-carboline in order to obtain a compound molecule with good activity.This thesis uses L-tryptophan as raw material.In the second chapter,a series of 6-aryl-β-Carbline were synthesized with the help of Suzuki reaction through the bromine atom as the functional handle.In the third chapter,the intermediates of 6-amino-β-carboline and 6-amino-5-chloro-β-carboline were obtained by nitrification and reductive amination,and then the intermediates were acylated twice with various cyclic anhydrides.After the condition screening,a series of 6-（N-imide）-β-carboline derivatives could be obtained by one-pot method under acetic acid reflux condition.A total of 71 new 6-substituted-β-carboline derivatives were synthesized.The target compounds were characterized by ¹H NMR,¹³C NMR and HRMS.The antitumor activities of 60 of target compounds in vitro were tested by MTT method.After that,the target compound was molecular-docked to understand its binding with the target protein,which could provide reference for the subsequent study on the structure-activity relationship to the antitumor activity of6-substituted-β-carboline derivatives.In summary,on the basis of related reports and previous studies,a series of 6-（C-C/C-N）-β-carboline derivatives with good anti-tumor activity have been synthesized in this thesis,providing a reference for improving the effects of C⁶and N⁹modifications on the anti-tumor activity ofβ-carboline derivatives.