Design,Synthesis And Biological Evaluation Of Shikonin Benzoyl Acrylic Acid Ester Derivatives Targeting Of Tubulin And EGFR Proteins

Cancer is one of the world recognized diseases that threaten human health mostly.Millions of people die because of cancer every year.and millions of people are diagnosed with cancer.The research on cancer has been one of the main directions of life science researchers around the world.Epidermal growth factor receptor(EGFR).as an important target of anticancer drugs.overexpressed in many tumor tissues.The overexpression of EGFR leads to the activation of the inner pathway of a series of tumors and further promotes the growth and development of tumors.There fore,drug targeting based on EGFR has become one of the research directions.EGFR protein signaling pathways including the mitogen activated protein kinase pathway the MAPK pathway and the anti-apoptotic AKT pathway,apoptosis,invasion and other physiological functions in tumor cells are closely related with these two signaling pathways.It is promising direction to research the drug inhibited tyrosine kinase activity of EGFR protein.With the deepening of clinical drug application and drug research.the disadvantages of single target drug gradually appear.and it is easy to form drug resistance and lose the original efficacy of drugs.so the multi target EGFR protein inhibitors have become a new research trendShikonin is natural medicinal active small molecule,which has good antitumor,anti-inflammatory and anti-bacterial activity.Strong cytotoxicity of shikonin has also limited its clinical application.Therefore,we use shikonin as the lead compound,the chalcone structure has the function of EGFR protein inhibits the introduction of the structure,combined with double target tubulin and EGFR inhibitory activity to active molecules.In the experiment of anti-proliferation activity,the inhibitory effect of compound PMMB-317 on four kinds of cancer cells was obvious,and the half inhibitory concentration of A549 cells was 4.37 ± 0.46?M.PMMB-317 induced apoptosis in A549 cells by a dose-dependent and time-dependent manner,it decreased mitochondrial membrane potential of A549 cells induced apoptosis;Caspase apoptosis related protein also shown that PMMB-317 could promote the apoptosis protein expression to induce cell apoptosis,such as cleaved Caspase-3,cleaved Caspase-9 and cleaved PARP protein,PMMB-317could arrest cell cycle in G2/M phase inhibited the polymerization of microtubules,and its effect was similar to colchicine;PMMB-317 can inhibit EGFR protein tyrosine kinase activity,blocking signal transduction downstream of mitogen activated protein MAPK pathway and anti-apoptotic kinase AKT pathway,promoting induce the cell apoptosis.Docking known from molecular simulation,PMMB-317 can simultaneously with EGFR protein(5HG8)and tubulin(1SA0)through the combination of a variety of forces;that by in vitro experiments,In addition.EGFR was also demonstrated in the downstream signal transduction protein in the verification process,a number of changes of apoptosis proteins and apoptosis of anastomosis,further evidence of the molecular interaction in tubulin and EGFR promotes apoptosis.PMMB-317 can act on the EGFR protein affect downstream signaling promotes cell apoptosis.This molecule is a potent inhibitor of tubulin and EGFR,and has a typical double targeting inhibitory function.To overcome the single target drug resistance of EGFR protein,it is important to obtain more effective antitumor drugs.