| The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression,including cell proliferation,apoptosis,angiogenesis,and metastatic speed.The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway.The results of a large body of preclinical studies and the early clinical trials thus far conducted suggest that targeting the EGFR could represent a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR.The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling. A number of small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity is in development.ZD1839 and OSI-774 are 4-anilinoquinazoline selective inhibitors of tyrosine kinase of EGFR,which are currently in Pase III and Phase II development,respectively. CI-1033 is an 4-anilinoquinazoline irreversible selective inhibitor of tyrosine kinase of EGFR that is currently in Phase I development.Preliminary results from Phase I and II trials in patients with advanced disease demonstrate that ZD1839 and OSI-774 have promising-5-clinical efficacy in patients with a variety of tumor types.In a further development of new 4-anilinoquinazoline selective inhibitors of tyrosine kinase of EGFR,we have done some work as down list:?An improved Niementowski reaction which was applied in preparing4(3H)quinazolinone------the critical intermediate of 4-anilinoquinazolines has beenstudied. Method: Five quinazolinone compounds, such as 6-X-4(3H)-quinazoinone ( X=NO2,Cl,Br J) and 1 -furfuryl-6-sulfarnide-7-chloro-4( 1 H)-quinazolinone(5),were synthesized by reaction of anthranilic acids with formamide accompanied by titrating with phosphoryl chloride. Results: When the improved Niementowski reaction was applied ,the reaction could go along well within 90-95癈. Compound 5 could even be prepared on the ice-bath condition.But the original Niementowski reaction needs the reaction temperature more than 175癈.(2) The course of the improved Niementowski reaction has been studied. Method: We selected N,N-dimethyl formamide as the reaction material instead of original reagent 梖ormamide in order to make the reaction halt in the intermediate phase and used NMR to identify the intermediate. Results: The course of the improved Niementowski reaction is similar to that of original Niementowski reaction.(D Using 6-niro-4(3H)-quinazolinone as the initial reagent, we synthesized a series of 4-anilinoquinazolines substituted with 6-nitro, 6-amino, 6-cinnamido or 6-malemido side chains. Among these compounds, 4-anilinoquinazolines substitued with 6-cinnamido or 6-malemido were designed by using principle of irreversible inhibitor of epidermal growth factor receptor .?The synthesized 4- anilinoquinazoline compounds has been rudimentarily screened by using A431 tumor cell line which overexpresses epidermal growth factor receptor and eternal normal NIH3T3 cell line as screening model. Method: A431 cells were plated out in Fi2 medium containing 10% fetal bovine serum at a-6-concentration of 104 cells/well in 96 well plates ,then cultured in the CO2 culturing tank.After 24h,they were given various concentrtions of 4-anilinoquinazoline compounds according to the plotting area on the plate.The cells growing status was observed through invert microscope everyday.The cultures would have been incubated for 4 days at 37癈 with 5% CO2.On day 5,each well was added 5mg/mL MTT and incubated continually for 4 h..Then,the upper solution of the wells was discarded gently.After this,every well was added 150 u L DMSO.Finally,the plate was surged for lOmin on Sunrise ELISA instrument.The OD values of each well was also detected at 570nm vs controlling...
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