Design,Synthesis And Biological Evaluation Of Irreversible EGFR Inhibitors For Overcoming Drug Resistance

Malignant tumor is a kind of diseases which causes serious damage to human health. Development of high-efficiency and low-toxicity drugs is one of the medicinal chemistry research emphasizes and hotspots recently.The epidermal growth factor receptor (EGFR) family is a group of receptor tyrosine kinases that mediates cell proliferation, survival, migration, and differentiation.At the same time, in different tumor cells it can be found that the overexpression of EGFR,which leds to the abnormal proliferation of tumor cells. There are a lot of small molecules inhibitors targeting the EGFR on the market and they have been put into clinical use.. But at the same time, the problem is that these drugs will lead to drug resistance in the process of treatment.The T790M mutation is one of the main causes of acquired drug resistance.Aiming at the problem of drug-resistant of EGFR inhibitors, This paper design and synthesis compounds which has the structure of 4-aromatic amino quinazoline and 3-cyano-4-aromatic amino quinoline as mother nucleus structures. We use two strategies and two kinds of new compound was synthesized.The first is introducing acrylamide with halogen atoms to the structure of 4-aromatic amino quinazoline or 3-cyano-4-aromatic amino quinoline mother nucleus. The second is the irreversible inhibitor based on the HDAC/EGFR/HER2 targets.In 4-aromatic amino quinazoline’s sixth site a functional group which can has electrophilic addition with cysteine and the pharmacophore of HDAC enzyme inhibition are introduced.Most of the acrylamide irreversible inhibitors including fluorine, chlorine atom have activity to the EGFR wild-type kinase inhibitory activity to a certain extent, some has good inhibitory activity. At the same time,they inbited the cell proliferation,including on the human epidermal carcinoma cell A431(with EGFR high expression) and Gefitinib-resistant cell H1975 to a certain extent. The irreversible inhibitors based on the HDAC/EGFR/HER2 targets have comparative inhibitory activity with Gefitinb to the A431 cells. The compounds, QWX-102、QWX-103、QWX-104, QWX-104 with the structure of hydroxamic acid, have better inhibitory activity than SAHA to the Hela cells which have high HDAC expression. The research of this paper provides the basis for the further optimization of structural modification and structure-activity relationship of the two kinds of compounds.