Synthesis、Preliminary Biological Evaluation And Molecular Docking Of The Antitumor Drugs TW91Derivatives

Molecular targeting treatment means when antitumor drug approach to the keytarget molecules of tumor, it can bind to receptors or mediate factors to reduce theexpression or activation of these receptors and downstream genes, thus can reversethe procedures of tumor differentiation, or inhibite proliferation of tumor vascularcells indirectly. Finally it can lead to apoptosis and necrosis of tumor cell. Sinceprotein kinases play a critical role in the most majority of signal transductionpathways, including cell metabolism, proliferation, differentiation, cell survival,angiogenesis and immune response. Therefore, by inhibiting protein kinases activitycan achieve good effect of cancer treatment. So it has become a focus to develop newprotein kinases inhibitors.In this paper, we synthesized a series of small molecular naphthalenecarboxamide and benzamide carboxamide derivatives through researching thestructure-activity relationship of listed tyrosine kinases inhibitors or drugs in clinicalstudies, and using computer-aided molecular docking technology. At the same time,we investigated the inhibition ability and structure-activity relationship of thesecompounds through in vitro activity screening and molecular docking. The results areas follows:(1) Design and computer-aid screening of naphthalene carboxamide andbenzamide carboxamide derivatives. We designed10compounds of naphthalenecarboxamide derivatives and29compounds of benzamide carboxamide derivativeswith the help of molecular docking between AutoDock4.2.5softwares and EGFR(PDB ID:4HJO).(2) Synthesis and structure identification of naphthalene carboxamide andbenzamide carboxamide derivatives. All the compounds were identified by NMR,HRMS and IR.(3).MTT experiments of Hela cells, human ECA-109cells and non-small lungtumor A549cells. We got14compounds with good activities and the most values ofIC50were below10μM. (4).QSAR studies of naphthalene carboxamide and benzamide carboxamidederivatives. Most of the free blinding energies among compounds and EGFR werebelow-9kcal/mol. Results showed that these compoumds were ideal candidate drugsas protein tyrosine kinase inhibitors.