Study On The Synthesis And Biological Activities Of Erlotinib Derivatives

Erlotinib is a protein-lanine kinase inhibitor that contains a quinazoline skeleton.Quinoline derivatives are present in natural alkaloids.Quinazoline skeleton is also an important structure in the pharmaceutical chemistry.Many compounds containing quinazoline structure show good anti-cancer,anti-bacterial,anti-inflammatory activities and so on.1,2,3-Triazole is an important pesticide and pharmaceutical pharmacophore,which has good biological compatibility and aromaticity.Over the years,1,2,3-triazole was often used as an important pharmacological group.Different substrates of the drug molecules were linked together via “click-chemistry”.After structural transformation,they showed a better activity.As an anti-cancer drug,erlotinib has drug resistance and adverse reactions.This thesis firstly discusses the current status of the tumor,protein peptidase kinase inhibitors and the biological activity of 1,2,3-triazole compounds.Secondly,twenty-one erlotinib-linked 1,2,3-triazole compounds were synthesized based on the active group splicing method,which used m-anilines,amino phenylacetylene and 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline as raw materials through diazotization,arylamino condensation and "Huisgen-click" reaction.We optimized the reaction conditions,including the screening of the catalyst,the solvent,the reaction charge ratio,the amount of catalytic loading and the temperature.The obtained optimal reaction conditions was in hand: the molar ratio of erlotinib to phenyl azide derivatives was 1:1.2,NaAsc 20 mol%,CuSO4.5H2 O 10 mol%,H2O:TBA:THF=1:1:1,80 oC.The reaction can be carried out smoothly with high yields.The new compounds were confirmed by NMR,HRMS,melting point and otheranalytical methods.Thirdly,erlotinib derivatives were evaluate the antifungal activities against Staphylococcus aureus,Bacillus megaterium(Gram-positive bacteria)and Escherichia coli(Gram-negative bacteria).According to the diameter of the inhibition zone,we selected some compounds with obvious antibacterial activity for further MIC test.The MIC results showed that when the aryl azide ring had an electron-withdrawing group,the activity of the compound was relatively good.The minimum inhibitory concentration of these 11 compounds were more than 512 ?g/m L,and the minimum inhibitory concentration of those 10 compounds was less than 512 ?g/mL.Among these 10 compounds,when the aryl azide ring had a F-substituted derivative(2-14),the activity was the best among the tested compounds with the minimum inhibitory concentration of bacteria 128 ?g/mL.Then,we tested the antimicrobial activity of 21 erlotinib derivatives against Botrytis cinerea,pepper anthracnose,Rhizoctonia solanicorn and corn leaf blight using the growth rate method.All compounds showed antifungal activity.Among them,compound 2-14 had the best activity against Botrytis cinerea and Rhizoctonia solani with the inhibition rate 35.7% and 37.6%,respectively.Compound 2-16 had the best activity against pepper anthracnose and corn leaf blight with the inhibition rates 36.4% and 37.1%,respectively.Finally,MTT methods were used to measure the activity of inhibiting liver carcinoma cells HepG2 in vitro.The results showed that some compounds had a certain inhibitory effect on HepG2 growth.Sample 7had significant activity on HepG2 with IC50 of 10.98 ?mol/L.We docked sample 7 with the EGFR protein molecule using computer simulation of molecular docking.The calculation was consistent with the measurement result.