Synthesis And Antitumor Activity Of 8 - Nitro - 5 - Arylbenzamide - Quinazoline Antiangiogenic Inhibitors

Cancer is the leading cause of serious threat to human health and life. The physiological process that are tumor growth, proliferation and metastasis is largely dependent on the new blood vessels to provide the necessary nutrients, cut off nutrition for the new blood vessels that could prevent the growth of malignant tumor cells. Therefore, the angiogenesis has become an important direction of new anti-cancer drugs. Tumor cells on its own the secretion of VEGF (vascular endothelial growth factor) on the vascular skin outside the main receptor VEGFR-2, stimulate and induce the formation and growth of new blood vessels. Thus, VEGF and the receptor of VEGFR-2become to a new target for cancer concern cell therapy and drug development.In the current, the hot study of anti-tumor drugs which have the novel structure about VEGFR-2inhibitor drugs.1. Based on the anti-tumor activities of the three fragments found in our previous isoquinoline imine compounds and clinical drug sorafenib structure, the subject of the proposed that design and synthesis of a class of isoquinoline imine nucleus of three fragments type VEGFR-2kinase inhibitor compound:2. With three fragments VEGFR-2protein kinase inhibitors that are small molecule compounds and amide compounds having pharmacological activity as the guide structure, the establishment of a5-aryl8-nitro-phenyl amide quinazoline antiangio genic inhibitors Scheme compounds. Synthesized from readily available starting material phenylene diamines a starting compound1, to get the Boc-protected compound2, compound2with an aromatic acid chloride3reaction and to get a compound that having an amide structure4, then to deprotection by TFA and get the compound5; mother nucleus structure4-hydroxy-8-nitro-5-chloro-quinazolin-6then substitute reaction with a compound5, and finally to get quinazoline of three fragments having a novel structure VEGFR-2protein kinase inhibitor compound7.The synthetic route has the readily available starting materials, simple operation, mild conditions and post-processing and simple. It is unreported that the synthetic route to gain23VEGFR-2kinase inhibitors small molecule compound libraries7a-7w, their structure have been confirmed by IR,’H NMR,13C NMR and HRMS.3. Small molecule compounds prepared in chick embryo angiogenesis in vivo model law was tyrosine kinase inhibitory activity test. The results showed compounds7c,7d,7e,71,7m,7o,7p,7q have good anti-angiogenic activities, IPP quantitative analysis showed that the compound71,7o antiangiogenic drugs inhibit the rate is higher than the positive control drug sunitinib.4. The above-mentioned compounds were anti-tumor cytotoxie activity test, and found that the most compounds on colon cancer cells (HCT-116) and (SW480) have a certain inhibitory activity. And in all compounds,7q,7o have similar cytotoxic activity and the positive control drug DDP.