Synthesis And Screening Anticancer Targets Of N⁹-N^9’ Linked β-carboline Dimer Derivatives

β-carboline alkaloids,originally isolated from Peganum harmala in 1841,are a class of natural and synthetic indole alkaloids with a tricyclic pyrido[3,4-b]indole ring system.Much research has been done on the design and development of β-carbolines as a new class of antitumor agents,and a large number of β-carboline derivatives have been prepared in search of agents that are more potent.β-carboline derivatives due to their widespread availability from natural sources,structural flexibility,quick reactivity and interaction with varied anticancer targets such as DNA(intercalation,groove binding,etc.),enzymes(GPX4,topoisomerases,kinases,etc.)and proteins(tubulin,ABCG2/BRCP1,etc.)have established themselves as promising lead compounds for the synthesis of various anticancer active agents.This is a further study on our group’s achievements about systhesis and bioactivity of β-carboline dimers.Firstly,a series of N9-N9’ linked β-carbolines are synthesized by PictetSpengler reaction and evaluated their anti-cancer activity against breast cancer line MCF-7 in vitro.In addition,the structure-activity relationship(SAR)analysis of β-carboline monomers and dimers are summarized.At last,the targets which β-carboline compounds interact with are screened by network Pharmacology and molecule docking.The results are as follows:1.34 compounds of β-carbolines are synthesized by Pictet-Spengler reaction.the number of β-carboline monomers are 14,and the dimers are 20.Based on tricyclic β-carboline skeleton,ester group at C-3,methoxy group at C-6,alkyl groups and aromatic groups at C-1 are added respectively.As for dimers,two monomers are linked at N9 to obtain dimer compounds.2.Inhabitory activity against MCF-7 of 34 compounds are evaluated in vitro.The result shows M12,M13,D10,D15,D19 exhibit significant inhibitory activity more than 80 percent,and the acvtivity of componds M8,M10,D9,D14 are very close to 80 percent.the structure-activity relationship(SAR)analysis of β-carboline componds shows that when there are suitable functional groups such as alkyl and aromatic groupes at C-1 will enhance activity of componds.And aromatic groups are better than alkyl groups.The ester group at C-3 position and methoxy group at C-6 positionwill enhance inhibitory activity of β-carboline compounds.Most of β-carboline dimers have higher activity than monomers.3.D10,the highest activity compound is selected as example.4 drug targets which D10 would potentially interact with are screened by network pharmacology and molecule docking.This four target genes are m TOR,AKT1,CCND1,ERBB2 respectivly.GO enrichment analysis shows that biological processes of anti-breast cancer focus on reproductive structure development,molecular function of anti-breast cancer is protein serine/threonine/tyrosine kinase and cellular component of anti-breast cancer is membrane raft.KEGG enrichment analysis indicates the pathway of β-carboline which can exert anti-breastcancer function is anti-cancer pathway.The association between expression of key genes and survival of breast patients is analysed by Kaplan-Meier Plotter database.The results show that the high expression of m TOR,ERBB2,CCND1 genes of breast patients have longer time to live than who are low expressed,and AKT1 has no relationship about the survival of breast patient.In conclusion a series of β-carboline compounds are synthesized in this study and evaluated inhibitory activity against MCF-7 in vitro.This study lays a foundation of β-carboline compounds as an anti breast cancer medicine.