Synsthesis And Anti-tumor Activity Of 2,4,5-trisubstituted Pyrimidines As Novel Aurora Kinase Inhibitors

Aurora kinases are a family of mitotic serine/threonine kinases, which have been implicated in several vital events in mitosis. Deregulation of Aurora kinase activity can result in mitotic abnormality and genetic instability, leading to defects in centrosome function, spindle assembly, chromosome alignment, and cytokinesis. So they have received significant attention as new targets for anticancer therapy. In this thesis, we designed and synthesized 16 2,4,5-trisubstituted pyrimidine compounds as Aurora kinases inhibitors, which were analogues of VX-680. They were also evaluated their antiproliferative activity and cell cycle effects, and the results showed that these compounds are generally more potent cytotoxicties against HCT-8, A-549, HeLa and Hep-G2 tumor cell lines than VX-680. Compound 52 showed the highest cytotoxicties with IC50 values of 3.0-10.0μM. Furthermore, flowing cytometric analysis exhibited that compound 52 indued cell cycle arrest in the G1 phase in HCT-8 cells. This series of compounds have potential value for development and further research about its anti-tumor activity and mechanism is undergoing.