Design,Synthesis And Study On The Antitumor Activity Of Novel Aryl Urea Derivatives As VEGFR Inhibitors

Malignant tumors have previously become one of the main causes of human death. In recent years, the incidence of cancer in our country also presents the trend of a rapid rise. Protein kinase inhibitor is a kind of important molecular targeted anti-tumor drugs, among which the receptor tyrosine kinase inhibitors have been the most widely studied.Vascular endothelial cell growth factor (VEGF) is currently known as the strongest and most active angiogenesis factor with the highest selectivity among the various angiogenic factors been discovered by now. VEGFR, the receptor for VEGF, is a member of the receptor tyrosine kinase superfamily. The VEGF/VEGFR signaling is considered as an attractive therapeutic target in recent years for the inhibition of tumor angiogenesis, and participates in the regulation of a series of physiological and pathological effects of the body. The signaling is critical to promote the formation of new blood vessels, and is also intimately related to the growth and metastasis of malignant tumor. VEGFR has three mainly subtypes known as VEGFR-1 (FLT-1), VEGFR-2 (KDR) and VEGFR-3 (FLT-4). The recent study reveals that KDR may be the main receptor of VEGF.Tivozanib, also known by KRN-951, is an oral VEGFR inhibitors. It has potent in vitro inhibitory activity aiming to VEGFR-1, VEGFR-2 and VEGFR-3. The results of the III phase of clinical trials of renal cell carcinoma showed that comparing to Sorafinib, the positive control drug, Tivozanib did quite well in many aspects such as progression free survival time, tumor response rate, and drug resistance, etc. Besides, Tivozanib has also been reported in other tumor treatment, such as lung cancer, gastrointestinal cancer and so on.In order to find antitumor drugs with better activity, we take Tivozanib as the lead compound, combining with existing research progress of our lab, aiming to the structure of the hydrophobic binding region and allosteric pocket to design the novel drug molecule. We retain the quinoline structure as the basic structure to combine competitively with the adenine binding sites of ATP. We’ve also done a lot of changes to see the effects of the antitumor activity:taking the substituted benzene (section B) as the hydrophobic binding group; introducing proper side chains into the quinoline structure; and replace the group that participate in the formation of urea.We take 7-(benzyloxy)-6-methoxyquinolin-4-ol as starting material. Then synthesize through different synthetic routes to get the key intermediate I-4a、 I-4b、I-8a、I-8b and I-8c. After that, with the key intermediates and intermediate II-1, II-2 and II-3, we have synthesized a series of novel aryl urea derivatives as VEGFR inhibitors,15 target compounds have been gained by now. And all these compounds have not been documented. The structures of all the 15 compounds were confirmed by H-NMR. In our experiments, we tried the different synthesis routes, and choose the one we thought was the best to finish this study. Except that, the reaction conditions were optimized.Finally, with the A549 cell line as subjects, all of the target compounds were tested, so that we can have a preliminary study on the in vitro antitumor activity of the compounds. As the existing results show us, that compounds X-01、X-02、X-06、X-07、X-09、X-10、X-11、X-13、X-14、X-15 showed significant in vitro activity, some even better than the positive control drug. So they are worthy of further studies.