Synthesis And Biological Activity Of Gefitinib Analogue Based On Molecular Modification Of Morpholine

The discovery of EGFR-TKIs greatly improved the survival time and quality of life of NSCLC patients.As the first listed EGFR-TKI,gefitinib has many advantages,such as high selectivity,short production time,long duration,cheap and used widely.But it has weaker inhibitory activity and drug resistance is a problem.According to the literature,the binding ability of the drug to EGFR determines its inhibitory activity to a certain extent,and drug resistance is also associated with it.On the mechanism of gefitinib,6-substituted morpholine groups shows no effect on the combination of drug and EGFR.To enhance the binding ability of drugs and EGFR,a series of groups with different electronegativity were introduced to the morpholine group of gefitinib and gefitinib analogues W1-W9 were designed.Using 2-amino-4,5-dimethoxybenzoic acid as the raw material,after cyclization reaction,demethylation,protection of the hydroxyl,chloride by thionyl chloride,coupling with aniline derivatives and deprotection a quinazoline parent nucleu formed.Finally,it was reacted with different morpholine derivatives to get corresponding gefitinib analogues.All gefitinib analogues were confirmed by 1H NMR,13C NMR,HPLC and MS.EGFR and EGFR positive cancer cell lines A431,MDA-MB-231 and A549 were used as subjects to test the extracorporeal biological activity of the gefitinib analogues.The results showed that nine gefitinib analogues had certain inhibitory activity to EGFR.Electronegativity of the morpholine side chain group and steric hindrance influence the inhibitory intensity.When the side chain group's electronegativity enhanced,the inhibitory activity also increased.But if the electronegativity reaches a certain level,inhibitory activity becomes weak.W4 which was introduced in hydroxymethyls in morpholine showed the strongest inhibitory activity.And when the side chain is too long,the steric hindrance is too large.It is not conducive to the combination with EGFR,and causing the inhibitory activity decreased significantly.The intensity of inhibitory activity to cancer cells has not been clearly identified.However,the inhibition activity to lung cancer cells has been significantly improved by introducing a side chain to morpholine when the structure is(S)-configuration.