Design, Synthesis And Bioactivity Of Selective B-Raf^V600E Inhibitors

Protein kinase, as known protein phosphatase, is a kind of proteinphosphorylation enzyme. It plays an important role in cell signal transductionpathways, which regulates cell growth, proliferation. Mitogen-activated proteinkinase signal pathway (MAPK) is one of the most important signal pathways in cells.The Ras-Raf-MEK-ERK signal cascade has received extensive attention for it playsan important role in the formation of human cancer. B-Raf is one of the Raf kinasefamily members. Compared with the other two members (A-Raf, C-Raf), B-Raf hashigher kinase activities and it is easy to activated. Recent results show that a varietyof human tumors, such as malignant melanoma, colon cancer, thyroid cancer, arerelated to B-Raf mutants. The most common B-Raf mutation occurs in the600amino acid residues of the active region, namely the glutamate substitution of valine(B-RafV600E). The mutation rate of B-Raf kinase is very high in the tumor, about7%-8%occur in human cancer with B-Raf mutations. It has been determined thatthe activation of B-Raf somatic mutations in melanoma rate is about66%, as35-70%in thyroid cancer, colon cancer is5-20%, about30%of ovarian cancer. Andthe activity of B-RafV600Eis nearly500times higher than that of the wild type B-Raf.Therefore, B-RafV600Ehas become one of the most important targets of humancancer.In this thesis, we got the compound30named7-[6-Methyl-1-(4-methyl-3-Trifluoromethyl-phenylamino)-isoquinolin-5-yl-ethynyl]-quinazolin-2-yl-aminethrough activity screened the existing small molecule compound library. Let it as thelead molecules, we designed and synthesized a series of novel B-RafV600Ekinaseinhibitors. Starting from the simple and accessible raw materials,21targetcompounds were finally synthesized, which were tested the structure-activityrelationship and bioactivity in vitriol. It revealed the structure activity relationship ofthis kind of molecules for the first time. Particularly, compound40inhibited thekinase activities of B-RafV600Ewith IC50value of8.9nM，and inhibited the cellactivities of COLO205and NCI-H460IC50values of1.92μM、0.88μM. Our workalso provides reference for inhibitor synthesis of B-RafV600Ekinase in the future.