Design, Synthesis And Biological Evaluation Of Salicylanilides Derivatives

The treatment of malignant tumors has been a worldwide problem for decade.Many studies show the main cause of cancerous probablely is the cell transductionpathway disorders cause cells to proliferate indefinitely. Therefore, the finding for keyenzyme of the related cellular signal transduction pathways and proliferation of tumorcell differentiation as drug screening targets, and efficient, low toxicity of newanti-cancer drugs has become an important direction of the research and development ofanticancer drugs today.In order to find new anticancer drugs, in this thesis, multitargeted tyrosine kinaseinhibitor class of anticancer drugs Lapatinib was listed as a model compound.According to the the scaffold hopping molecular fragment theory, we design andsynthesis the new salicyloyl aromatic amines multitargeted tyrosine kinase inhibitorclass of anticancer drugs. All target compounds’ biological activity and thestructure-activity relationship were discussed.In this thesis, sixteen feruloylagmatine analogues were designed and synthesizedwhile their chemical structures were confirmed by1H NMR,13C NMR, ESI-MS andIR．Biological activity screening of the target compound were tested by MTTcolorimetry, while gefitinib were used as control drugs. sixteen target compounds invitro tumor cell proliferation inhibitory activity. The preliminary activity test resultsshow that the target compounds of four kinds of tumor cells(A549, MCF-7, SGC-7901,Bel-7402)have different levels of inhibitory activity. Compound5c to10c with lapatinibfragment as Side-chain showed better inhibitory activity than the positive controlgefitinib. And a pyridine ring on the nitrogen atom in posision2of the compound (5a~9a) inhibitory activity on tumor strain was significantly better than the nitrogen atom inthe3, the compound (5b~9b). When the side chain as neratinib and lapatinib fragment,R is5chloro-substituted (9a,9c), activity are better than other substituents. When the side chain as neratinib fragment, consider substituted yl electric effect, R is4superiorinhibitory activity against A549cell, by electron donor groups (6a,7a), an electronwithdrawing group (5a,8a).The compound9a with the IC50of the four kinds of cellswere9.76μM,9.63μM,15.32μM,12.92μM.