Design,Synthesis,and Anti-tumor Evaluation Of Novel Ureas As Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors&Pyrrolic Compounds Construction

Angiogenesis,the process of new blood vessel formation from pre-existing vascular networks by capillary sprouting,is an important pathway for normal processes and pathological processes.Among the multitude of endogenous factors driving angiogenesis,vascular endothelial growth factor(VEGF)and its receptor tyrosine kinase VEGFR-2 are key regulators.It has been demonstrated that the growth of primary tumors and their subsequent metastasis are angiogenesis-dependent processes.Hence,we can block the growth of a solid tumor by suppressing its blood supply via the inhibition of VEGFR-2.This thesis mainly focus on the design and synthesis of vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors and their antitumor activity.Guided by the cocrystal information of sunitinib and sorafenib,we have synthesized three different series of VEGFR-2 inhibitors,totally 41 compounds.All compounds were screened for inhibition of HUVEC cell and tumor cell lines.To our delight,cellular assay identified that the first series compounds and several compounds of the other series exhibited potent cellular inhibitory activity.The result revealed that some compounds possessed favorable cellular potency than the positive reference substance sunitinib.With the result we had,we analyzed the structure-activity relationship to offer detailed information for further design and synthesis of novel inhibitors of VEGFR-2.In the third part of the thesis,we developed the methodologies to afford several heterocyclic compounds.Herein,we discovered a facile approach and "one-pot"multicomponent way to provide pyrroline and pyrrole derivatives.In summary,we have developed a new general and practical synthetic protocol for the efficient assembly of polysubstituted pyrrolines and pyrroles from nitroallylic acetates and mesylated 2-aminoethanones,which would provide an attractive strategy for the synthesis of pyrrole drug intermediates.