Design, Synthesis And Anticancer Evaluation Of Benzoimidazol-2-methylamides And 1,4-Dihydroisoquinolin-3-ones Derivatives

The Receptor tyrosine kinases (RTKs) are a class of receptors with tyrosine kinase activities, which can be activated by corresponding ligands such as insulin, growth factors or cytokines. When stimulated by these ligands, RTKs self-phosphorylate tyrosine residues of their own, and then, they transfer extracellular signal to the cytoplasm by followed convening and phosphorylating of downstream signaling proteins. RTKs can mediate sevaral important cellular signal trasction pathways to regulate cell proliferation, differentiation, migration, metabolism and other processes. Furthermore, it is confirmed that tumor invasion, metastasis, angiogenesis, resistance to chemotherapy are closely related to the abnormal expression of RTKs. Therefore, RTKs are considered as significant anti-cancer drug targets. The first chapter of this thesis reviewed on the RTKs and their inhibitors.Based on the knowledgement of RTKs and the signal transduction pathways mediated by them, we designed and synthesized a class of benzoimidazol-2-formamide peptide-like inhibitors from the perspective of multi-target inhibitors to RTKs. We synthesized a total number of 136 benzoimidazol-2-formamides,48 of which have been characterized by MS and 1H NMR. Furthermore, they were used for the biological evaluation in vitro. The biological evaluation results indicated that most synthesized compounds showed a slightly selective inhibition to HepG2 tumor cells on the concentration of 30μmol/L. Six of the tested compounds showed good antiproliferative activities, compound 4.3.7 was found to have the most potent cytotoxicity against HepG2 and KB with inhibition values of 35.6% and 12.5%. Structure-activity relationship showed that when there were aromatic amino acids on R1 position, compounds showed better inhibition to tumor cells, while heterocycle acids on the R2 position proved to be more favorable substitute groups.The isoquinolinone is an important heterocyclic scaffold widely found in many natural alkaloids and pharmaceuticals that exhibit antitumor, antimicrobial, antiplasmodial activity and noncompetitive inhibition to AMPA receptor. The wide range of biological and pharmacological importance of isoquinolinones promoted us to prepare new derivatives of these compounds utilizing a simple and efficient method. We reported an efficient method for the synthesis of 4-substituted-1,4-dihydro isoquinolin-3-ones employing an intramolecular Heck reaction, providing full regio-and stereoselectivity. Most of the synthesized compounds showed potent antiproliferative activities against tumor cell lines.