Synthesis And Biological Activity Test Of Indole Alkaloid Derivatives In Uncaria Based On Photocatalysis

ObjectiveIndole derivatives which have special physical and chemical properties in Uncaria are important pharmaceutical intermediates and organic raw materials.Indole alkaloids can be obtained by extracting active components from Uncaria or chemical synthesis,while organic solvents may act with active components in the extraction process of traditional Chinese medicine,which makes them lose their original utility.Considering the limited resources of traditional Chinese medicine,many people began to try to obtain its active components by chemical synthesis.Indole alkaloids are a class of compounds with indole scaffolds and can be widely used in the fields of pharmaceuticals,pesticides,perfumes,dyes,food and feed additives and so on.Due to its important value in application,the synthesis and application of indole compounds has caught a lot of attention in organic chemistry.Developing of a convenient and environment friendly method is of great methodological and pharmaceutical interest to us。MethodsIn previous studies,our group investigated whether KOt-Bu/DMF can promote the free radical reaction initiated by β-aminoalkyl radicals to synthesize nitrogen-containing heterocyclic compounds.However,in the early experiments of solvent screening and substrate expansion,it was found that the substrate range was narrow and the yield of the target product was not high.Inspired by the synthesis of certain substrates in this type of reaction,we designed and synthesized a series of indole derivatives based on previous research.This work introduces a simple,flexible method for indole synthesis via intramolecular photocyclization of carbonyl and tertiary amines without relying on photocatalysts mainly.During the experiments,we screened common solvents and expanded substrates in the standard reaction.Finally,the optimal synthetic route for the synthesis of such indole derivatives was selected,and 33 compounds were obtained.To evaluate the safety of these compounds,we tested the cytotoxicity of 16 of these indole derivatives on lung cancer cell A549 using MTT colorimetry.Taking the group without indole compound as the control group,the blank medium group as the blank group,and the different compound concentration groups as the administration groups.The cell inhibition rate of each dose concentration was calculated by the formula.ResultsThe proposed photocyclization was first evaluated with no photocatalyst added in NMP solvent under Ar and room temperature,with the product obtained in 57%yield.Considering the indole synthesis contains photocyclization and the subsequent dehydration,The results display that the addition of PTSA can slightly increase the yields.Furthermore,the reaction was also carried out smoothly under sunlight.The anticipated product was acquired in 78%yield.After measuring the cytotoxicity of 16 indole compounds by MTT method。It was found that compared with the control group,9 compounds were more cytotoxic,and 1 compound with less cytotoxicity.ConclusionIn this work,we discovered an intramolecular photocyclization for indole synthesis without relying on photocatalysts.A wide range of functional indoles were prepared with moderate to excellent yields under mild reaction conditions.It provides a new path for the synthesis and modification of indole derivatives.