Synthesis And Activity Evaluation Of Novel Tyrosine Kinase Inhibitors And Synthesis Of New Anti-Radiation Molecules

The work of this paper is divided into two parts:The first part of the work is mainly the design and synthesis of novel protein tyrosine kinase inhibitors.Protein tyrosine kinase?PTK?is closely related to tumor signaling and has been used as a target for antitumor drugs.c-Met as a small molecule inhibitor binds to receptor hepatocyte growth factor?HGF?to activate tyrosine kinase,and induce a series of biological effects.The specific membrane receptor of HGF is the expression product of proto-oncogene c-Met.The abnormal activation of HGF / c-Met signaling pathway is found in a variety of tumor tissues.This abnormal activation is involved in and regulates the occurrence,development or metastasis of these tumors.Blocking HGF /c-Met signaling pathway can effectively inhibit tumor cell growth and invasion.SU5416 is an effective inhibitor of HGF,which can block HGF-induced Hep G2 liver cancer cell invasion and metastasis through a large number of experiments.A series of structural studies were carried out on this basis,and a new compound L029 which showed good activity in both enzyme and cell experiments was screened by active screening and pharmacological evaluation.In this paper,a series of L029 derivatives was designed and synthesized by reduction or replaced with the side chain3-dimethylamino-1-propane,methyl acetate,methyl propionate in its active H and other sites for the poor solubility for L029.The synthetic compounds were finally screenedfor tyrosine kinase activity.The results of the screening found that compounds TM03,TM04,TM08,TM10,TM15,TM11 K had significant inhibitory activity at 100mM,where TM11 K was the potassium salt of TM11 and had a stronger potent effect on PTK than L029.Compounds TM03,TM04,TM08,TM10,TM15,TM11 Na also had significant inhibitory activity at 1m M concentration.The second part of the work is mainly the optimization of the synthetic route of the new anti-radiation molecule DBIBB and the synthesis of its halogenated derivatives.LPA₂ is a class of G protein-coupled receptors,and the non-lipid agonists of this receptor have the effect of treating acute radiation sickness.DBIBB as a class of specific LPA₂ agonists has the effect of reducing acute radiation-induced bone marrow damage and gastrointestinal injury,both of which are the most sensitive organs for high-dose radiation exposure.In this paper,DBIBB was synthesized and its original synthetic route was optimized,the heating time of the reaction was shortened,the use of concentrated sulfuric acid was avoided,and the yield was improved.The new synthetic route was not reported in the literature laying the foundation for its large-scale production.It is reported that the activity of DBIBB fluorinated derivatives and chlorinated derivatives is much higher than that of DBIBB.In this paper,the synthesis methods of the two were improved and expected to achieve amplification preparation which laid the foundation for further research on the new anti-radiation molecules.In conclusion,12 new compounds were synthesized and eluted with L029 as the lead compound,and several compounds with good tyrosine kinase inhibitory activity were screened out,which provides an important reference for further structural optimization of these compounds.At the same time,DBIBB and its fluorinated andchlorinated derivatives were prepared,and the synthetic route of the three was improved,which laid the foundation for further research on new antiradiation molecules.