Design,Synthesis And Antitumor Activity Research Of Novel Indole Compounds

Indole is an important type of nitrogen-containing heterocyclic ring,which exists in many biologically active molecules in nature.Indole derivatives play an important role in the field of drug therapy,showing antitumor,antibacterial,antiviral and other pharmacological activities.In recent years,it has been reported in the literature that some indole compounds containing fused heterocycles also have anti-malarial and anti-hepatitis C virus effects.In order to improve biological activity,this paper used the splicing principle to introduce pharmacophore groups such as pyrimidine and pyrimidotriazole on the indole ring,and prepared new indole compounds through chemical reactions and explored their antitumor activity.The specific research introduces the following works:Preparation of target compounds:2,4-dichloropyrimidine or 4H-1,2,4-triazol-3-amine were uesd as the starting materials,the pyrimidine-indole biaryl compounds and the pyrimidotriazole-indole biaryl compounds were prepared by common organic synthesis reactions..In addition,aromatic aldehydes or substituted isatins were used as starting materials,and undergone intermolecular condensation with amino to form imines.In the next step,a cascade cyclization reaction occurred under Ag（I）catalysis to prepare pyrano[4,3-b]indole or[1,3]oxazino[3,4-a]indole series compounds.The characteristic of this method was that a single configuration of fused heterocyclic indoles could be regionally selectively synthesized by controlling the reaction temperature.Moreover,two ring systems could be constructed in one step under mild conditions,which had the advantages of simple operation,wide substrate range and good functional group compatibility.Evaluation of antitumor activity:Through MTT screening experiments,it was found that pyrimidine-indole biaryl compounds had antitumor activity against MGC-803,PC-3,EC-109,PC-12 and MCF-7 cells.Among them,compounds 34c and 34k showed excellent antitumor activity against PC-3 cells,with IC₅₀ values of4.10μM and 2.75μM,respectively.In particular,compound 34i had good antitumor activity against these five cell lines,and compound 34i showed the best inhibitory activity against LSD1,with the inhibition rate of 55%and the IC₅₀ value of 1.03μM.Compounds 50b and 50t showed the best inhibitory activity against BRD4,the inhibition rate reached 91%,the IC₅₀ values were 2.07μM and 2.26μM,respectively.Compound 50t had good antitumor activity against MGC-803 cells,with the IC₅₀value of 8.28μM.Further study on the mechanism showed that compound 50t could inhibit the expression of c-Myc protein and related proteins of glycolytic pathway.It also reduced the production of lactic acid and ATP,where the reduced ATP level further led to the activation of the AMPK signaling pathway and induced MGC-803cells apoptosis in a concentration dependent manner.In summary,this paper had prepared 103 indole compounds with completely new structures.,and developed a new method for the synthesis of fused heterocyclic indole compounds.Some indole compounds had high antitumor activity.Compound50t exerted an antitumor effect by inhibiting the expression of c-Myc protein and its glycolytic pathway related proteins.