Design, Synthesis Of Diaryl Ether Tyrosine Kinases Inhibitior And Study Of Their Antiaumor Activities

Tumor is an abnormal proliferation of tissue as a result of abnormal growth or division of cells, which can be caused by genetic mutations. Some of the key enzymes in tumor cell differentiation and cell proliferation-related signal transduction pathway as a target for drug screening and found that selectively act on specific targets efficiency, low toxicity and specificity of the new anticancer drugs, tyrosine kinase inhibitors has become an important direction of research and development of anticancer drugs today.In this study, we combinedcomputer-aided design with the literature analysis, based on the diaryl ether, we substitute of urea with amide structure by bioisosterism, design and synthesis four derivatives of compounds with amide, which were screened for anti-tumor activity in latter experiments. HepG2, A549and HT-29were selected for the screening study.The results showed that:(1) In the five compounds:N-(mono-substituted phenyl)-4-phenoxybenzamide showed excellent antitumor activity,4-substituted better than3-substituted; the activity order of4-substituted is electron-donating> weak electron-withdrawing> strong electron-withdrawing, among of them,-OH (YSM-20) is the best. Noteworthy,1,2,3,4-tetrahydro-1-naphthylamine (YSM-09) which belongs to N-alkane-4-phenoxy-benzamide construction showsa great activity in this study, the compound isracemic mixture, in the configuration relationship analysis, we found the S-configuration (YSM-14) is better than the R-configurations (YSM-13).(2) MTT experiment found that YSM-14, YSM-15and YSM-20has a significant inhibitory effect to the cell proliferation of HepG2, A549and HT-29, and IC50value are2.36,1.50,4.56μM for YSM-14,2.57,5.48,20.04for A549,8.00,3.43,0.03μM for YSM-20.(3) Tablet colony formation experiment shows that YSM-14on HepG2and YSM-20on A549has greatly inhibitory effect.(4) Cell cycle experiments show that A549, HepG2and HT-29can be blocked in S phase and G2phase by YSM-20respectively.In this study, we based on molecular modeling and docking technology and structure-activity relationship analysis, designed a series of compounds. After screening experiments, we obtain two compounds with excellent activity such as YSM-14and YSM-20. The study provided an important research base for the design of anti-cancer targeted drugs which based on the tyrosinekinase inhibitor.