Design,synthesis Andanti-tumor Activities Ofaryl Urea Derivatives As Novel Tyrosine Kinase Inhibitors

Following cardiovascular disease, cancer is currently the second major cause of death in the world; and in our country, cancer has taken the first position over all reasons leading to death. As a result, cancer preventing and treatment must be taken as an important task in China. Nowadays, operative treatment, chemotherapy and radiotherapy are the major routes to treat cancer. However, the traditional drugs of chemotherapy are cytotoxic which usually bears properties of nonselective and severe side-effect. Therefore, it is urgent to develop novel anti-cancer drugs with high activity and low toxicity. In recent years, with the development of molecular biology and cell biology, it is possible to design and prepare drugs targeting at special molecule or gene which is called targeted drug therapy. Recently, many effective targets such as protein kinase have been identified.Protein tyrosine kinases(PTKs) are enzymes that can transfer a phosphate group from ATP to a protein in a cell. The phosphorylation of tyrosine residues in turn cause a change in the function of the protein that they are contained in.PTKs are important regulators of intercellular communication controlling cell growth, proliferation, differentiation, survival and metabolism.Therefore, anti-cancer drugs targeting at PTKs have attracted special intetest in recent years.According to different structure, the PTKs can be divided into two groups that is Receptor Tyrosine Kinases(RTKs) and Nonreceptor Tyrosine Kinases(NRTKs)。Now about 60 different kinds of RTKs has been identified and can be divided into 20 subfamilies while NPRKs have about 30 different types and can be divided into 10 subfamilies.Ras/Raf/MAPK pathway, PI3K/PKB pathway and JAK/STAT pathway constitute the major signaling pathway of PTK.During the past 30 years, many tyrosine kinase inhibitors(TKIs) have been developed and shown high efficacy in clinic use. Sorafenib is a multi-target small molecule tyrosine kinase inhibitor which is developed by Bayer and Onyx.It was approved by FDA for the treatment of treatment of primary kidney cancer (advanced renal cell carcinoma) at the end of 2005, and also for advanced primary liver cancer (hepatocellular carcinoma) in 2007.We chose sorafenib as lead compound in order to obtain novel TKIs with higher activity and lower side effect. Based on the analysis of structure activity relationship of sorafenib and its analogs, we decided to keep the urea group and transform the pyridine ring of sorafenib into quinoline ring; meanwhile, we use lactam group to replace the former amide group and add two methyl groups to enhance electronegative environment.To increase hydrophobicity, it is considered essential to bring halogen on Ring B.Thus we designed and synthesized 12 novel compound with the structure of aryl urea. All the structures were identified by 1H-NMR and MS .Our target molecules were started with 2-methyl-2-phenylpropanoic acid, followed by esterification, nitrification, reduction reaction of nitro group, substitution reaction,the synthesis of quinoline ring, chlorination, nucleophilic substitution, reduction reaction of nitro group and the synthesis of urea group.We used Hep-G2 to evaluate the activities of target compounds in vitro. The results showed that all the 12 compounds had some inhibition activity. Compound1,2,3,4,5,6,8,9,12 showed better anti-tumor activity in vitro then sorafenib. Especially, compound 6 showed the best activity at about the half level of sorafenib. So it is worthy of further study.