Design, Synthesis And Bioactive Evaluation Of Anticancer Agents As EGFR Inhibitors

Cancer is a primary cause of death in the world. In the United States25%deaths is due to cancer. Though we spend amounts of effort and money to research, cure advanced disease has not been achieved. So it is crucial to find novel cancer agents with new mode of action for saving lives. EGFR (epidermal growth factor receptor), a growth-factor-receptor tyrosine kinase, plays a vital role in tumors proliferation, survival, migration, differentiation and metastasis of many tumors. In addition, many researches have demonstrated the EGFR can be seen as a rational target for anticancer. Erlotinilb and gefitinib which could inhibits EGFR was approved as antitumor agents. In this paper we designed and synthesized two series of compounds and evaluated for theirs bioactivities as inhibitor of EGFR.(1) Due to pyrazole, thiazole and naphthalene ring potent biological activities and low toxicities, we designed and synthesized a series of compounds containing pyrazole, thiazole and naphthalene ring as antitumor agents. A series of compounds which contain pyrazole, thiazole and naphthalene ring (1a-7a,1b-7b,1c-7c,1d-7d) are prepared and evaluated for anti-proliferative activities against BGC823, Hela and HepG2cell lines and their EGFR inhibitory activities. All compounds characterized by’H NMR, ESI-MS and elemental analysis. Compounds1d and5d were provided with single crystal X-ray structural analysis. Those inhibitor dispalyed strong antitumor activity, especially, compound2-(3-(3,4-dimethylphenyl)-5-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (7d) showed the most potent inhibiting Hela cell line activity with IC500.86μM and exhibited the most potent EGFR inhibitory activity with IC50of0.12pM. Structure-activity relationship (SAR) analysis showed that the anti-proliferative activity was affected by benzene ring-substituent (-OCH3>-CH3>-H>-Br>-Cl>-F). The result of biological assays demonstrated that anti-proliferative activities of the synthetic compounds were probably correlated to their EGFR inhibitory activities. Besides, in cytotoxicity and inhibition to Hela cell migration assay displayed7d no cytotoxicity on human macrophage and could inhibit Hela cell migration. Docking simulation of compound7d into EGFR active site showed that naphthalene ring of7d with LYS721formed two p-π bonds, which enhanced antitumor activity.(2) A series of caffeic acid amides (D1-D17) which contain2,3,4,5-tetrahydrobenzo[b][1,4] dioxocine structure were synthesized. The structures of compounds were confirmed by1H-NMR, ESI-MS and element analysis. Besides, compound D9((E)-N-(4-Ethoxyphenyl)-3-(2,3,4,5-tetrahydrobenzo [b][1,4] dioxocin-8-yl) acrylamide) was determined by single-crystal X-ray diffraction analysis. All of those compounds were reported for the first time. In anti-proliferative and EGFR inhibitory activities assays showed most of compounds exhibited good antitumor activities. Compound D9showed the best activities (IC50=0.79μM for HepG2and IC50=0.36μM for EGFR). In general, the2,3,4,5-tetrahydrobenzo [b][1,4] dioxocine structure and the p-position of benzene ring in amides were important positions to enhance compound’s biological activities. In addition, apoptosis assay, cytotoxicity and inhibition to HepG2cell migration got positive result. Docking simulation of compound D9into EGFR active site showed that D9with MET793and LEU1001to form two H-bonds, which could enhance the binding affinity and increased antitumor activities. This study shows that D9was a novel compound that can be potent antitumor inhibitor of EGFR.This study shows that7d and D9were novel compound that can be potent antitumor inhibitor of EGFR.