Design,Synthesis And In Vitro Anti-tumor Activity Evaluation Of 4-phenoxyquinoline Derivatives

Malignant tumors are a common and frequently-occurring disease that poses a serious threat to human health.They are characterized by abnormal proliferation of cells or mutant cells.At present,human deaths due to malignant tumors account for the second highest rate of all disease deaths,second only to cardiovascular and cerebrovascular diseases.Due to the shortcomings of existing anti-tumor drugs,such as high toxicity and drug resistance,the development of targeted anti-tumor drugs has always been the focus and development of global pharmaceutical companies and governments.The completion of the human genome sequencing work and the continuous understanding and elaboration of the disease mechanism in molecular biology have enabled the discovery of drug discovery from the traditional animal model screening to the precise design of targeted drugs for key enzymes or receptors in the pathogenesis mechanism.The molecular inhibitor specifically binds to the target protein,selectively blocking the excessive proliferation of the tumor cells,thereby effectively controlling and treating the disease.Among the molecularly targeted drugs,the development of protein tyrosine kinase inhibitors is particularly attractive,and the compounds with quinazoline and quinoline as drug skeletons are most ideal.Based on the literature and combined with the structure-activity relationship of the commercially available quinazoline and quinoline structure protein tyrosine kinase inhibitors,three series of 27 unreported compounds were designed and combined with computer simulation results to finally synthesize 18 unreported 4-phenoxyquinoline compounds.The target compounds are obtained by condensing 3-fluoroaniline,3-methoxyaniline and 2-methoxyaniline with EMME,condensation,cyclization,hydrolysis,decarboxylation,chlorination and alkylation reaction in 6 steps.Their structures were confirmed by ¹H-NMR.At the same time,the optimal reaction conditions for each reaction were explored and the process optimization of each step was carried out and the reaction conditions of the key reaction steps were discussed.Finally,the target compound was tested for anti-tumor activity by MTT colorimetric assay.The results showed that compound 6c showed good anti-tumor activity against SGC-7901,BEL-7402and A549 cell lines(IC₅₀0 values were 15.59μM,7.10μM and 7.07μM respectively),the activity was better than gefitinib(IC₅₀0 values were 16.83μM,23.61μM and 14.77μM,respectively);compounds 6b,18a and 18c showed moderate suppression against SGC-7901,BEL-7402 and A549 cell lines.For the three series of target compounds（X=F,OCH₃,Y=H;X=H,Y=OCH₃）,when the substituent R is attached to the electron-withdrawing group,the inhibitory effect on the three cells is better the electron-donating group.The anti-tumor activity of electron donating group is connected to C-8 position of the quinoline was better than that of C-7position against three cell lines;the inhibition effect of electron withdrawing group linked at C-7 position of the quinoline was superior to that of C-8 position against three cell lines.