Design,Synthesis And Anti-tumor Activities Of Aiyl Quinoline Derivatives As Novel Tyrosine Kinase Inhibitors

With the pollution of the environment and lifestyles changed, the incidence of cancerhas quickly increased,which now has surpassed heart and cerebrovascular diseases andbecome the “first killer” to human’s life.At present, the treatment of cancer include mai-nly three methods: surgery treatment, radiotherapy and chemotherapy. Doing surgery tr-eatment and chemotherapy at the same time is the mainstream method of cancer thera-py. However,the differentiation and complexity of tumor mechanism make the same an-ticancer drugsin the treatment of various tumors play different outcomes. Now the rese-archers realized that if we want to improve the efficacy of cancer treatment, we shouldfind out the mechanism of the cancer. As the the development of molecular biology andcell biology, molecular targeted drugs are hot in the treatment of cancer. The researchfocus on anticancer drugs has turned to the closely related targets which determine thetumor cells’s development. Among the various antitumor targets, protein kinase hasbecome an international hot study for anticancer drugs.Protein kinase, also known as protein phosphatase (PTKs), can catalyze γ-phosphatetransfer to the residues of the protein tyrosine kinase. It can also catalyze a variety of thesubstrate proteinstyrosine residues’s phosphorylation, which plays an important role incell growth, proliferation, differentiation. According to whether have cell membranereceptor or not, PTKs were divided into two groups: NPTKs and RTKs. NPTKs mainlytake the src gene product as representative, in addition, Yes, Fyn, Lck, Fgr, Lyn, Fps/Fesand Ab1and so on are also included. RTKs mainly have EGFR famliy, insulin receptorfamily, PDGF/MCSF/SCF receptor family and FGFR family. Recently, scientistsfound that the dysfunction of the PTK can lead to value-added cell disorder and has closely linked with the development of tumors. Therefore, looking for novel tyrosinekinase inhibitors is worthy for further study.In recent years, there are several tyrosine kinase inhibitors which have been marketed orentered clinical studies. Under the cooperation between the company of Bayer andOnyx, Sorafenib, which is the first multi-targeted tyrosine kinase inhibitor, roles intyrosine kinases receptor and protein serine/threonine kinase receptors, was approvedby FDA in2005for the treatment of renal cell carcinoma and hepatocellular carcinoma.But its high price limits its widespread use.In order to obtain the tyrosine kinase inhibitor which have independent intellectualproperty rights, a series of PTKs inhibitors compounds were designed and synthesized,based on the lead compound of sorafenib by principle of bioisosterism and structuraloptimization. The pyridine ring of sorafenib was replaced by quinoline ring; the amidegroup meanwhile was replaced by lactam group, adding two methyls in order to incre-ase its electronegativity. At the same time, we added halogen groups in order to increaseits hydrophobicity and biological activities. As is known to all, ureido is the key groupof the Sorafenib’s biological activities, so we introduced a carbonyl in order to increasethe formation of hydrogen bonding capacity and improve its biological activities on thebasis of it.Based on the above design,12target compounds have been synthesized and evaluatedin vitro against Hep G2. The results showed that12target compounds had some certa-in activities. Among them, the biological activities of compound9,10,11,12showedequivalent bioactivities with sorafenib.