Asymmetric β-carboline Dimers Constructed By Pictet-spengler Reaction And Its Antitumor Activity Evaluation

β-carboline derivatives are a class of organic alkaloids with tricyclic structure widely distributed in nature and have a variety of pharmacological activities.As a novel carboline derivative with twoβ-carboline core,β-carboline dimers show similar biological activities with carboline monomers,among which the anti-tumor activity is the most significant.In this article,The dimerization was conducted with L-tryptophan methyl ester hydrochloride and aldehyde derivatives by Pictet-Spengler,26 newβ-carboline dimers were synthesized in this way.The vitro antitumor activity of the compounds was evaluated and structure-activity relationship was summarized.Using molecular docking technology forecasted feasible binding of the compounds to the DNA topoisomerase Ⅱα.The main research contents were found as follows:1.Twenty-six newβ-carboline dimers were synthesized from L-tryptophan methyl ester hydrochloride by Pictet-Sengler cyclamation,oxidative dehydrogenation,ester reduction,primary alcohol oxidation,ester hydylolysis and other steps.The structures were determined by ¹H NMR,¹³C NMR,2D NOESY and HR-MS.2.The inhibitory activities of 26 compounds against human cervical cancer cell（Hela）human lung cancer cell（A549）and human liver cancer cell（HepG-2）in vitro were evaluated by CCK-8 assay.Six compounds showed high inhibitory activity against Hela cells(IC₅₀<10μM)Among them,compounds D13b and D10b showed the strongest anti-tumor cell proliferation ability.The value of IC₅₀ for Hela,A549 and HepG-2 tumor cells was between2.60-8.49μM.3.The antitumor structure-activity relationship of 1,3-disubstitutedβ-carboline dimers was preliminarily summarized.The main structure-activity relationship were as follows:The effects of C³ substituents on the activity was as follows:CH₂OH>CONHNH₂>COOMe;The C¹configuration in C ring of tetrahydro-β-carboline played an important role in the activity.The activity of（1S,3S）-β-carboline dimers showed higher activity than（1R,3S）-β-carboline dimers.4.The physicochemical properties of 26 compounds were calculated.The physicochemical properties of C³alcohol-substituted D10a/b-D13a/b and C³hydrazine-substitutedβ-carboline dimers D14a/b-D17a/b basically complied with the Lipinski rules.With the help of molecular docking technology,the possible targets of the compound with topoisomerase Ⅱαwere predicted.The docking results showed that compound D13b formed hydrophobic interaction,π-πstacking interaction,electrostatic interaction and hydrogen bonding interaction with the amino acid residues of receptor DNA topoisomerase Ⅱα,thus stably wrapped in the active pocket.While compound D13a with（1R,3S）configuration only formed hydrophobic interactions and weak hydrogen bonding interactions with a few residues when it bound to the receptor DNA topoisomerase Ⅱαand part of the groups completely exposed to the outside of the receptor binding pocket.The results of the D13b and D13a docking experiments further confirmed the results of the structure-activity relationships of anti-tumor activity.As mentioned above,the 26β-carboline dimers synthesized generally with anti-tumor cell proliferation ability,which enriched the structural diversity ofβ-carboline dimers.The anti-tumor structure-activity relationship and the results of molecular docking experiments could provide theoretical guidance for the further synthesis ofβ-carboline derivatives,and provided a reference for the research and development of new natural product anti-tumor activities.