Design,Synthesis And Biological Activity Of Epidermal Growth Factor Receptor Tyrosine Kinases Inhibitors

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which is catalytically active and under tight regulatory control. EGFR and its family memebers besides ErbB2/Neu/HER2, ErbB3/HER3and ErbB4/HER4play important roles in regulating a number of cellular processeess including cell proliferation, survival and migration. Dysregulation of its activity is strongly associated with tumorigenesis and cancer patients with altered EGFR activity tend to have a more aggressive disease, associated with a poor clinical prognosis. Therefor, EGFR is a rational target for anti-cancer strategies.In this thesis, we designed and synthezied a panel of4,6-disubstituted pyrimidine compounds aming at EGFR and a series of bio-probes based on4-anilinoquinazoline and4-anilinoquinoline scaffords, which were evaluated for their biological activity in vitro. And also we carried out virtual screening against EGFR and evaluated for the43compounds. At last, we applied structure-based3D quantitative structure activity relationships (3D-QSAR) method to a series of inhibitors and discussed the possibility of elaborated more potent EGFR inhibitor.1. A total of seventeen4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-(3-substituted-phenoxy)pyrimidine derivatives was synthezied and evaluated for their biological activity. As shown from kinase assay, the derivatives substituted with acrylamino, cyanoacetamino,6-(4-amino)pyrimidinyl-amino and phenoxyacetamino, were the more potent compounds which possessed IC50values37/29nM,48/38nM,61/42nM and65/79nM against EGFR/ErbB-2, respectively. Among of them, two derivatives substituted with acrylamino and6-(4-amino)pyrimidinyl-amino, showed the best antiproliferative activity and their IC50values against A431/SKOV-3cells were3.25/0.89μM and4.24/0.71μM, respectively.2. By using of docking, we performed virtual screening against SPECS database and picked out43compounds for biological evaluation. In the kinase assay,13novel inhibtors were discovered with inhibitory activitiy at micromole order of magnitude, and7compounds inhibited EGFR kinase activity with IC50values lower than10μM. Among of them,3-{[1-(3-chloro-4-fluorophenyl)-3,5-dioxo-4-pyrazolidinylidene] methyl}phenyl2-thiophenecarboxylate, particularly, was the most potent inhibitor possessing the IC50value of3.5μM. In the antiproliferative assay, 4-[4-(benzyloxy)benzylidene]-1-(3-chloro-4-methylphenyl)-3,5-pyrazolidinedione and2-amino-3-(1,3-benzodioxol-5-yldiazenyl)-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one were of better selectivity against cell lines, which also possessed kinase inhibitory activity with IC50values8.6μM and5.3μM, respectively.3.4-anilinoquinazoline and4-anilinoquinoline scaffolds bearing a2,2,6,6-tetramethylpiperidine-N-oxyl(TEMPO) were synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and A431cell lines. Compared to their corresponding parent compounds, all of the new compounds bearing a TEMPO showed more efficient inhibition for EGFR and A431cells.4. Structure-based3D-QSAR method was applied to a series of EGFR inhibitors in order to obtain the interaction models between EGFR protein and small melocular inhibitors. The information gained from3D-QSAR provided useful information to elaborate the better EGFR inhibitors.