Design,Synthesis And Biological Evalution Of Tetrahydroisoquinoline-based Diary Urea Compounds For Suppressing VEGFR-2 Signaling Pathway

Tumor angiogenesis plays an important role in tumor cell proliferation and metastasis.As the most potent and specific angiogenic factor,VEGF regulates the angiogenesis and vascular migration,and is overexpressed in a variety of malignant tumors,thereby being closely related to the growth,metastasis,and prognosis of tumors.VEGFR-2,belonging to receptor tyrosine kinase family,mediates many biochemical and physiological processes for neovascularization through binding to VEGF.Thus,inhibition of VEGF/VEGFR-2 signaling is considered as an effective strategy for battling malignant diseases.Urea moiety is an important pharmacophore in surpressing VEGF/VEGFR-2signaling pathway.Meanwhile,tetrahydroisoquinolines exhibite potent anti-proliferative activity.In this thesis,according to the pharmacophore strategy,a novel biaryl urea hybrid was obtained by combining diaryl urea with tetrahydroisoquinoline fragments.19 new tetrahydroisoquinoline-based diary urea compounds were designed,synthesized,and structurally determined by ¹H NMR,¹³C NMR and MS.Moreover,the biological activities of them were evaluated.The inhibitory effects of the target compounds on the proliferation of A549,MCF-7 and PC-3 cells were detected by MTT assay.The effect of the target compound on the VEGF/VEGFR-2 signaling pathway were evaluated by IF assay.In addition,the effect of target compounds on HUVEC tube formation was determined by tube formation assay.The results showed that,both compounds 9k and 9s exhibited the strongest antiproliferative activity and were superior to the positive control gefitinib.The compounds 9k and 9s inhibited the autophosphorylation of VEGFR-2 and downregulated the VEGFR-2 expression by immunohistochemistry.And the compounds9k and 9s had a strong inhibitory effect on tube formation.