Design, Synthesis And Sar Study Of1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one-based C-Met Kinase Inhibitors And Novel CXCR4Inhibitors

c-MET is a cell surface receptor for the hepatocyte growth factor (HGF). Normalactivation of c-Met kinase is essential for wound healing and embryonic development.c-Met has been found to be overexpressed or mutated in human cancer,which hasbeen correlated with metastasis and drug-resistance.Naphthyridin is widely applied inmedicinal chemistry as an ubiquitous scaffold, which displays a broad range ofbiological activities such as anti-virus, anti-bacterium and anti-tumor activity.We haveidentified asmall molecule c-Met kinase inhibitorLXM-22with1,3,5-trisubstituted-1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, whichdisplayed effective inhibition against both the TPR-Met phosphorylation in theBaF3/TPR-Met cells and the growth of TPR-Met tranformed BaF3cells.These resultsdemonstrated1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one target c-Met-mediatedsignal transduction pathways.In order to improve the potency of the new chemotype c-Met kinase inhibitors,based on the binding modes, we designed two classes of1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one-based c-Met inhibitors by introducing diffferentsubstituents at positions N-3/C-5or N-1/C-8as Type I and Type II c-Met smallmoleculoe inhibitors, respectively.By establishing efficient synthesis, we haveobtained3,5-or1,8-disubsituted1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-onederivatives (35compounds totally), leading to the identification of effective newstructure c-Met inhibitors. The best c-Met kinase inhibitory activity is exemplified by3,5-disubstitutedderivative2-3bwith an IC50=2.0μM, and1,8-disubstituted derivative2-2b with an IC50=3.9μM.Significantly, the Type II inhibitor2-3f displayedantiproliferative effect on the non-small lung cancer cells MKN45that contain anoverexpression level of Met gene. The premiliary structure-activity relationship indicated that the naphthyridin fragmentinteraction withhinge region play animportant role.CXCR4is a highly reserved G-protein coupled7-tranmembrane chemokinereceptor. It has only one natural ligand, namely CXCL12(SDF-1). The interaction ofSDF-1with CXCR4played an important role in a number of physiological processes:maintaining the cellular migration, homing the bone marrow and immune cells to sitesof inflammation., coreceptors for HIV entry into host cells, metastatic spread andindirectly regulating the growth and/or survival of several types of cancers.Starting from a clinically studied CXCR4antagonist AMD070, we havedesigned and synthesis a series of CXCR4inhibitors based on quinazoline scanfoldinspired by the binding mode with CXCR4. Then, we have gotten a inhibitor withIC50(SDF-1induced Ca2+-signals)of650nM. This have providedalead compound ofnew structure CXCR4inhibitors.