Chromanone Skeleton Splicing Oxide Indole Derivatives And Their Preparation Methods And Biological Activities

Cancer,as a problem with death rate second only to cardiovascular disease,has been widely concerned by all mankind.The currently commonly used anti-cancer drugs have relatively large side effects.Therefore,it is imperative to find anti-cancer drugs that are highly effective and have low side effects.In the reported studies,many natural products have good anti-tumor activity and can be used as the basic skeleton in drug synthesis.After modifying their structure,target compounds with multiple biological activities can be obtained.The chromanone skeleton is a focus of attention of researchers,with antibacterial and anti-tumor biological activities.In addition,oxidized indole compounds are also a hot spot for researchers.They have good anti-inflammatory and anti-tumor activities.Even though they have been studied by scientists for a long time,they still have a lot of research space because of their extensive biological activities.Therefore,if researchers want to find a lead compound skeleton with good biological activity,it is an important way to modify and transform the skeleton structure of natural compounds.In the first part of this thesis,based on the principle of drug skeleton splicing and transition designed for the synthesis of new drugs,the chromanone skeleton and the oxidized indole skeleton are spliced to synthesize new chromanone skeletons and spiro-epoxy indole compounds.The synthesized new compounds can Provide material basis for biological activity screening.The[3+2]cycloaddition reaction of trifluoromethylated oxidized indole compound and different substituted chromone tricarboxylic acid under DMAP catalysis occurs to synthesize trifluoromethyl-spiroepoxyindole-chromone Class compound.By screening the reaction conditions,26trifluoromethyl-spiroepoxyindole-chromanone compounds(3a-3z)were synthesized under optimal conditions.The synthesized compounds were determined by single crystal diffraction configuration,the molecular structure was obtained by nuclear magnetic resonance,and the relative molecular weight was confirmed by high-resolution mass spectrometry.It has good yield(70%?80%),diastereoselectivity(dr>20:1),has four continuous stereoisomeric centers,including an efficient four-substituted carbon.This reaction has a wide range of substrates,and the substituents on the chromone skeleton and the oxidized indole skeleton have no obvious influence on the synthesis of the product.Whether it is an electron-donating substituent or an electron-withdrawing substituent,high yield can be obtained.Selective product.When the nitrogen of isatin is protected by methyl 3a,ethyl 3b or benzyl 3y,it has relatively good reactivity to react and obtain high yield and diastereoselective compounds.In the second part of the work,chromone 3-hydroxymethyl reacted with(Boc)₂O,followed by a Michael addition cyclization reaction with 3-isothiocyanate indole oxide under the catalysis of tertiary amine DABCO to form a new type Bispiropyrrolidone oxidizes indole dihydrochromone compounds.After screening conditions,the optimal reaction conditions were obtained:dichloromethane was used as the solvent,DABCO was used as the catalyst,and the reaction was carried out for 10 minutes.A new type of bispiropyrrolidone oxidized indole dihydrochromone compound was obtained,and 11such compounds were synthesized.Compound.With this method,the target compound can be efficiently obtained.The synthesized compound contains the spirocyclic dihydrochromone skeleton and the spiropyrrolidone oxide indole skeleton,and has 4continuous stereo centers,including 2 spirocyclic rings,quarter Carbon Center.Among the 11 compounds synthesized,the yield is 70%?87%,and the dr value is 4:1?2:1.This reaction route is economical,environmentally friendly,and efficient,and it also provides a new method for the construction of dispiropyrrolidone oxidized indole dihydrochromone compounds.This reaction route is economical,environmentally friendly,and efficient,and it also provides a new method for the construction of dispiropyrrolidone oxidized indole dihydrochromone compounds.The third part of the work is to use the MTT method to evaluate the anti-tumor activity of the synthesized compounds in vitro.The positive control drug is cisplatin,which is commonly used clinically and has broad-spectrum anti-cancer activity.The cell line is human chronic myeloid leukemia cell line K562 cell line,and synthetic trifluoromethyl-spiroepoxyindole is taken.Six of the compounds were tested for in vitro anti-tumor activity.The results show that compounds 3i',3k'and 3n'have a certain degree of inhibitory effect on the proliferation of K562 cells.Because of the 6measured activity data,it is impossible to summarize the structure-activity relationship of the compound on the anti-cell proliferation,but it can explain the trifluoromethyl-spiroepoxy indole-chromanone skeleton compounds can be used as lead compound skeletons for in-depth research,accumulating some types of compounds for the potential drug molecule library.