Studies On Synthesis And Anti-tumour Activities Of1-aryl-1,2,4-triazolin-5-ones And Its Derivatives

Objective:Chemical medicines for traditional cancer therapy are mostly Cytotoxic drug, which have defect of severe side effect, low selectivity and easy to cause drug-resistance. Based on3D structure of special target, novel anti-cancer compounds which were high effect and low toxicity were anticipated to be developed, and they can inhibit multiple protein targets.Content:EGFR, c-kit, BCR-ABL kinase, Raf kinase and PKB play a significant role in tumour genesis and development. Based on the structure of these enzyme, Firstly the5representative structure were chose; Secondly1-aryl-1,2,4-triazolin-5-ones were used as lead compound to design ligands, these ligands and positive medicine were virtually screened by molecular docking to choose compounds through docking result and synthetic factor, these compounds would be synthesized in the next step. Finally, the compounds were synthesized, and their anti-cancer activity were tested.Methods:EGFR, c-kit, BCR-ABL kinase, Raf kinase and PKB were chose as target protein; Sequence alignments and3D structure fitting were taken by AlignX module of Vector NTI Suite9.0and Swiss PDB Viewer respectively to identify phylogenetic relationship. The designed ligands were dockinged to the five protein molecule through Glide module of Schrodinger, then the result were evaluated by Gscore to identify target compounds; Using p-substituted phenylhydrazines as starting material, compounds were synthesized by5-8steps reactions; Anti-cancer activities were evaluated by detecting the proliferation toxicity of target compound to human tumour cell, through MTT chromatometry.Result:1PKG,1UWJ,1VEB,1XKK and1K1F were identified as representative structures of the five receptors respectively for docking;121ligands were designed for docking, and16target compounds were acquired through virtual screening. At the end,20chemicals was gained by organic synthesis; In pharmacology research, most1-aryl-1,2,4-triazolin-5-ones derivative could inhibit human tumor cells in vitro, among them compounds LB1, LB8, LB15and LB16could inhibit tumor significantly. In addition, a novel reaction about4-methoxylphenylhydrazine hydrochloride was found, and its reaction mechanism was studied.Conelusions:The virtual screening model of anti-cancer activity has been built. Target chemicals were acquired through molecular modification and virtual screening based on docking method. Some of the synthesized target compounds have anti-toumour effect. The results of this research show that it is a practical way to design novel drugs on the basis of the structure of essential enzymes.