Biphenyl Replace 1,2,4 - Oxadiazole Class Of Small Molecule Pkb Inhibitor Design And Synthesis

With the discovery of upstream regulators and downstream substrates of the protein kinase PKB, its physiological function and role particularly in the formation and development of tumor , have been constantly revealed. PKB have become a focus of many scientific researchers. To PKB-mediated pathways, some kinds of inhibitors of different mechanisms have been designed and synthesized.This dissertation described the research process of a new class structure of the PKB inhibitors. The dissertation consists of two chapters. In the first chapter, some literatures were reviewed. The current research on PKB and its inhibitors was described. The second chapter described the design and synthesis of a 1,2,4-oxadiazo-le class of small molecule PKB inhibitors containing biphenyl structure .The first chapter is divided into four sections. The first section gave a detailed description of the structure of PKB's three major domains: PH domain, kinase domain and regulate domain. The second section introduced the biological function of PKB and described the role of PKB in cell metabolism, cell survival, cell cycle regulation and transcription regulation. In the third section, we described the activation process of PKB and how it promoted the formation and development of tumor through its substrates, after being activated. In the fourth section, the research on current PKB inhibitors were introduced. According to the different suppression mechanisms, several kinds of PKB inhibitors and their QSAR were described, such as phosphatidy-linositol analog inhibitors, pseudosubstrate inhibitors, allosteric PKB inhibitors, ATP-competitive inhibitors, PI3K/PKB-pathway inhibitors and inhibitors of mechanism unknown.The second chapter is divided into three sections. In the first section, the design of the 1,2,4-oxadiazole containing biphenyl structure class of small molecule PKB inhibitors were introduced. Torrey Pines Institute for Molecular established a computer screening model. According to the model, a preliminary design of the structure was conducted. The synthesis of the 1,2,4-oxadiazole containing biphenyl structure class of small molecule PKB inhibitors was described in the second section. We chose the reasonable routes, and 25 compounds were synthesized. Most of them are new compounds. The third section detected the cellular activity of parts of compounds and gave a preliminary discussion of QSAR.