Research On The Multi-Component Reaction Syntheses And Anti-tumor Activities Of Five-Member-Aza-Heterocycle-Contained Compounds

Aza-heterocyclic compounds are a class of important heterocyclic compounds with various biological activities and functions.They are widely used in the fields of medicine,agriculture,chemical and material.Multi-component reactions(MCRs)are an ideal reaction mode that conforms to the concept of green chemistry.MCRs have the advantages of simple operation,high efficiency,fast building structural complexity and diversity of compound libraries and atom economy,which are widely used in organic and medicinal chemistry.This dissertation focuses on the multi-component reaction syntheses and biological activities of five-memberaza-heterocycle-contained compounds.On the one hand,this dissertation focuses on the development of MCRs for the synthesis of pyrrolo[2,3-h]quinolines and 1,2,4-triazol-3-ones.On the other hand,this dissertation focuses on the study of anti-tumor activities of dihydropyrrol-2-ones(DHPs),the products of a four-component reaction(4CR)that we previously developed.The dissertation contains the three parts as follows.The first part is on the development of a new three-component reaction(3CR)for the synthesis of pyrrolo[2,3-h]quinolines.Pyrrolo[2,3-h]quinolines possess various bio-activities.However,the reported methods for their preparation suffer from certain drawbacks such as harsh reaction conditions,multi-step processes,low yields and narrow substrate scopes.We developed a 3CR for the synthesis of two new series of dihydropyrrolo[2,3-h]quinolines 2-4 and 2-9,using but-2-ynedioates,4-aminoindoles and aldehydes or isatins as the starting materials and water-dimethyl sulfoxide mixtures as the solvent.The 3CR could be conducted under catalyst-free and mild conditions,and afford 29 products in 28-70%yields.In addition,the dihydropyrrolo[2,3-h]quinoline 2-4a could be quantitatively oxidized into new pyrrolo[2,3-h]quinoline 2-10a at room temperature using Cu(NO3)2 as an oxidant.This work provides simple and efficient synthetic methods for further research on the bio-activities and other applications of pyrrolo[2,3-h]quinolines.The second part is on the development of a new MCR for the synthesis of 1,2,4-triazol-3-ones.1,2,4-triazol-3-ones have important applications in the fields of medicine and agriculture.Nevertheless,the reported synthetic methods suffer from many drawbacks such as multi-step processes and unavailable starting materials.Herein,23 2,4-disubstituted 1,2,4-triazol-3-ones 3-4 were synthesized in 32-67%yields via an I2-sulfuric acid-promoted MCR,using cheap and readily available formaldehyde,amines and hydrazines as the starting materials and dimethyl sulfoxide as the solvent.This work developed a simple and efficient synthetic method for the synthesis of 1,2,4-triazol-3-ones,which is beneficial to further study on the bio-activities and other applications of this class of compounds.The third part is on the study of anti-tumor activities of DHPs.Cancer is the second leading cause of death globally and the development of efficient small-molecule anti-cancer drugs is a hot research area in medicinal chemistry.We found that DHPs have good anti-tumor activities through the high throughput screening.Here,20 DHPs 4-5a-4-5t were designed and synthesized by the 4CR that we previously developed to study their anti-tumor activities against MCF-7,RKO,HeLa and A549 cancer cell lines.It was found that DHP 4-5a displayed the best antiproliferative activity against A549 cells(IC50=1.9μM).4-5q showed the best antiproliferative activity against RKO cells(IC50=0.8μM).4-5r-4-5t showed satisfactory antiproliferative activities against all of the tested cancer cells(IC50=0.9-3.9μM),of which 4-5s has the best activities(IC50=0.9-2.4μM).The structure-activity relationship of DHPs indictate that R4=3-MeO-4-OHPh is crucial for the antiproliferative activity against RKO cells.When R4 group combined with the appropriate R1,R2 and R3 groups,the compounds have good antiproliferative activities against all of the tested cancer cells.The study on the anti-tumor mechanisms indicated that DHP 4-5q is a G0/G1-phase arresting agent inducing cell apoptosis by decreasing the levels of cyclin D1 but increasing the levels of p53 and p21 in cancer cells.This work is of great significance to promote DHPs as new anti-tumor drugs.