Synthesis And Inhibitory Activity On MV-4-11 Of Benzofuro[3,2-c] Quinoline Derivatives

Polyheterocycles are common skeleton structures in clinical drugs and organic materials.Although benzofuro[3,2-c]quinoline derivatives have been extensively studied in photoelectric materials,they have rarely been reported as biologically active compounds.This thesis focuses on the construction of benzofuro[3,2-c]quinoline skeleton and the investigation of their anticancer activity.The following results were obtained:Part One:Study on synthetic method for construction of benzofuro[3,2-c]quinolinesThis thesis developed a new synthetic method for constructing benzofuro[3,2-c]quinolines,namely 3-（2-methoxyphenyl）quinolin-4（1H）-one as the starting material,the key intermediate 2-（4-chloroquinolin-3-yl）phenol was generated by one-pot chlorination/demethylation reactions in situ,and then followed by base-catalyzed intramolecular cyclization,the final product was yielded.The yield of two-step reactions can reach 96%and 88%respectively.The functional group tolerance experiment found that whether it was benzofuro or quioline part,the substances with electron-withdrawing substitution（halogen）and electron-donating substitution（methyl and trifluoromethoxy）can obtain high total yields,reflecting the good substrate university of the new method.Compared with the previously reported synthetic methods,the new strategy for constructing benzofuro[3,2-c]quinolines is mild and avoids the use of metal catalysts and dangerous reagents.Part Two:Preliminary investigation on biological activity and derivation of benzofuro[3,2-c]quinolinesPreliminary anticancer activity of the synthesized compounds was explored.The inhibitory effects against RPMI 8226（multiple myeloma cell line）,SUM 149（breast cancer cell line）,T47D（breast duct cancer cell line）,and MV-4-11 cell lines（acute myeloid leukemia cell line）of benzofuro[3,2-c]quinoline derivatives were tested.The results indicated that the compounds showed good inhibitory against MV-4-11 cell line.Among them,compound 5 had the best inhibitory activity with IC₅₀ value of 0.12±0.044μM.At the same time,it showed good selectivity to human peripheral blood mononuclear cells（PBMC）（SI=79.5）,suggesting that the compound had relatively weak toxicity.Furthermore,17 new benzofuro[3,2-c]quinoline derivatives were designed and synthesized,and then their inhibitory activities against MV-4-11 cell lines were evaluated.It was shown that the structural modification at the 9-position,including hydroxymethyl etherification and the introduction of diamine substituents were beneficial to improve the inhibitory activity.These results further clarified the structure-activity relationships,and had accumulated a certain research foundation for the potential application of such structural compounds in the discovery of lead compound of antileukemia drug.