Desig, Synthesis And Preliminary Study On The Antitumor Activity Of Novelquinoline VEGFR Kinase Inhibitors

In recent years,the number of cancer has increased dramatically.According to statistics,every 6 minutes in China there is a person diagnosed with cancer patients.Cancer is not only a major challenge facing China,it is a worldwide problem.Molecular targeted therapy can specifically act on tumor cells,block its growth,metastasis,induce apoptosis,and finally inhibit or kill tumor cells.In the known targeted anti-tumor small molecules,the small molecule anti-tumor drugs targeting angiogenic factor VEGF and its receptor VEGFR are the hotspots in recent years.The design,synthesis and evaluation of antitumor activity of VEGFR kinase inhibitors are the focus of this research.As a very important class of VEGFR kinase inhibitors,there are a numberof quinoline drugs listed,and some drugs in the pre-clinical or clinical research stage,such as Lenvatinib,Tivozanib and so on.Tivozanib is a potent,specific VEGFR kinase inhibitor that exhibits strong inhibitory activity against VEGFR1?VEGFR2?VEGFR3.Compared with sorafenib,there is an advantage in the treatment of renal cell carcinoma,including progression-free survival,tumor response rate and drug resistance.Tivozanib has also made good progress in the treatment of a variety of other tumors.However,there are some side effects,such as elevated blood pressure,some patients with sound disorders,etc.And because of its poor water solubility,it is often through the preparation of hydrochloric acid monohydrate method to increase the polarity.In order to find a better anti-tumor drug with better activity,better polarity and less toxic side effects,the subject of Tivozanib as the lead compound,combined with the relevant literature research,based on the work of the original laboratory,the structure of drug molecules is replaced by the principle of bio-electronic isostatic and the principle of splicing.Retention of quinoline nuclei as a basic skeletal structure,N(1)on the quinoline ring and N-H on the Cys917 skeleton on the hinge region form intermolecular hydrogen bonds.Chlorobenzene at the 4-position of quinoline nucleus is combined with the large hydrophobic chamber II region of the acceptor active chamber.In addition to retaining the substituent Cl atom,it is also attempted to replace with the F atom or remove the halogen atom substituent,to examine the difference between the halogen atom substituents and the presence or absence of effects on themolecular activity of the drug;The methoxy group at the 7-C position is replaced by 3-pyrrolyloxy or 3-morpholinopropoxy and which interact with the III region of the active chamber.The terminal urea structure or amide structure is expected to occupy the structural pouch,enhance the efficacy and drug selectivity.Therefore,in the choice of terminal group of urea groups with reference to the structure of sorafenib and levofibanide,the following design:(1)retention of isoxazole structure;(2)docking different substituted phenyl,such as meta-trifluoromethyl,meta-methoxy or other large steric hindrance to obtain high activity.On the basis of structural design,two synthetic routes were designed with4-hydroxy-6-methoxy-7-ethoxyquinoline as the starting material.The five key intermediates and 15 related intermediates were obtained by substitution,stripping,affinity substitution and so on.The synthesis of 12 target compounds was successfully completed by stitching principle and practice.The structure was identified by 1H-NMR.We used MTT assay to study the antitumor activity of the compounds in vitro and HepG2 and Huh7 were used as the subjects.The results showed that compounds such as compounds T-1 to T-8 showed significant in vitro activity,even better than those of positive control drugs,especially compounds T-1,T-2,T-3 and T-4 Well,it is worth further study,but also for the further development of VEGFR kinase inhibitors provide a reference.