Development And Synthesis Process Research Of Novel Aurora Kinases Inhibitors With Study Antitumor Activity

Cancer is one of the major diseases,which is threatening human survival and hardly to treatment.The method of using small molecule antitumor agents for which targeting the proliferation process of cell that is a very effective way of treatment for the cancer.In the signal transition of cancer cell proliferation,the use of targeting kinase inhibitors in small molecular with antitumor activity are applicable for discovery of the clinic medicine for cancer patients.However,because of the drug resistance of the aurora inhibitor,curative effect is hardly to realized.So the research for novel aurora inhibitor with new structure scaffold is urgently needed.The compounds based on quinazoline and pyrimidine have been becoming the prefered scaffold on antitumor agents.In our research,we use the quinazoline and pyrimidine scaffolds as the lead compounds to further modification which is tremendously applicable.In this research,we use the quinazoline and pyrimidine as the basic scaffolds,reasonable design the compounds and explore the new methods to synthesize the novel compounds.Furthermore,we test the antitumour activity of synthesized compounds and research on the synthetic process of the active compounds,so that we can develop a new class of aurora kinase inhibitors.The key points were discussed as follows:1.By taking 4-chloro-6,7-dimethoxyquinazoline as starting material,the 4-substituents of the scaffold were modified and then synthesized 19 kinds of target compounds with 4-N-methyl and-N-methoxy group for antitumor.All of the 19 compounds were identified by 'HNMR and 13CNMR.2.We use 4-chloro-6,7-dimethoxyquinazoline as starting material,for which modify the main structure of the 5-subsittuents aidded by the metal-coupling assistant method.3.By using 4-Fluorocinnamic acid as the internal standard substance to establish the 19F nuclear magnetic resonance(NMR)quantitative method for quantifying the gefinitib.4.MTT assay was used to evaluate the biological activity in the target compounds with MCF-7,A549,HepG2,SY5Y 4 kinds of tumor tissues,which used gefinitib as the positive control drug,and found that most of the compounds had moderate inhibitor effect on these 4 kinds of tumor cell lines.5.Study on the synthesis process of the compounds with well antitumor activity in the target compounds.6.By using 5-bromo-2,4-dichloropyrimidine as starting material to realize the Ullman reaction with copper catalyst that design and synthesize 10 novel compounds with the structure of pyrimidine imidazoleby cycling reactions,all the coumpounds were identificatied by 1HNMR.