Synthesis And Anti-tumor Activity Of β-carboline-3-nitrogen-containing Heterocyclic Derivatives

In nature,β-carboline alkaloids are widely distributed,including all kinds of terrestrial animals,plants and marine life.Studies have found that such alkaloids have neuropharmacological activities such as anti anxiety,antidepressant,antispasmodic,anticonvulsant,sedative,analgesic,and pharmacological activities such as anti-tumor,antimalarial,antiparasitic,and anti AIDS.Some of them have been proved to have high activity,low cytotoxicity and high solubility,which is of great significance for the development of new drugs.This article introduces some active groups for structural optimization through the principle of pharmacological group splicing.Based on the research foundation of the preliminary work of the research group,this topic is based on the chemical structure ofβ-carboline,combined with existing literature reports,1,3,4-oxadiazoles and 1,2,3-triazoles were introduced R³ position ofβ-carboline.and a batch of high-efficiency and low-toxicity derivatives were screened out as candidate compounds to carry out the drug-forming evaluation.In the second chapter,L-tryptophan was salted and then aromatic with different aldehydes to obtain connected with different substituentsβ-carboline derivative.After N⁹-alkylation,hydrazine hydrolysis of ester,condensation with triphosgene and other reactions,29 target compounds were prepared.The third chapter is still using L-tryptophan as raw material,through the N⁹-alkylation,hydrazine hydrolysis of ester,hydrazine reduction and other multi-step reaction synthesis of N⁹ position with different substituents and R³ position with amino groupsβ-carboline intermediate.Finally,the cyclization reaction with different arylketones producesβ-carboline derivatives of 1,2,3-triazole.23 target compounds were prepared.The structures of the target compounds synthesized in the above two chapters were confirmed by ¹H NMR,¹³C NMR and HRMS.The antitumor activity of 49 synthesized target compounds was tested in vitro by MTT colorimetry.To evaluate their anti-tumor activity against five kinds of cancer cells in vitro:lung cancer cells（A549）,gastric cancer cells（BGC-823）,colon cancer cells（CT-26）,liver cancer cells（Bel-7402）and breast cancer cells（MCF-7）.After studying the structure-activity relationship,it can be seen that:In the second chapter,when isopropyl and 2-chlorophenyl are introduced at R¹ position,the anti-tumor activity is significantly enhanced;When benzyl and 4-fluorobenzyl were introduced into R⁹ position,the antitumor activity would also be significantly improved;The anti-tumor activity of R¹ position is 2-chlorophenyl>4-methoxyphenyl,4-methylphenyl;The sequence of antitumor activity at R⁹ position is 4-fluorobenzyl>benzyl>n-butyl.In the third chapter,when R¹ is a methyl substituent,R⁹ has no substituent,and R³ is a 4-nitrophenyl and3-trifluoromethylphenyl substituent,the compound exhibits excellent antitumor activity;When R¹ has no substituent,R⁹ is benzyl substituent,and R³ is 3-methylphenyl,4-fluorophenyl,3-trifluoromethylphenyl substituent,these compounds have certain inhibitory effect on tumor cells;When R¹ is isopropyl substituent,R⁹ is methyl substituent and R³ is phenyl,the compound shows good antitumor activity.In summary,by comparing the compounds in the two chapters,it can be seen that the overall anti-tumor activity of the compounds in the second chapter is higher than that of the compounds in the third chapter,and one of the compounds shows excellent inhibitory activity on a variety of human tumor cells(IC₅₀ value is lower than 10μM),such as compounds C6b,C6l,C6o have certain potential for developing new intermediates or lead drugs of anti-tumor drugs.Molecular docking shows that the compounds synthesized in this thesis can bind to target proteins 4AGD,4FK3 and 6JOK through hydrogen bonding,hydrophobic interaction andπ-πinteraction.