Design, Syntheses, Bioactivity Test, And Modeling Studies Of Protein Kinase B Inhibitors And The Research Of Biginelli Reaction

Protein kinase B (also known as PKB/Akt) is a good drug target for cancer therapy. A series of inhibitors with different mechanisms have been found and used for cancer treatment. Among these inhibitors, ATP competitive inhibitor, allosteric inhibitor, ATP-independent PKB inhibitor and pseudosubstrate inhibitor are currently the most widely studied PKB inhibitors. However, due to the high homology of amino acid sequence between PKB subtypes and different AGC kinases, the development of PKB inhibitors targeting PKB has been hampered by lacking of PKB-specific and isoform-specific inhibitors.The study of the selective inhibition mechanism of kinase can provide the basis for the design of selective inhibitors. By evaluating the stability of kinase-inhibitor complex and the affinity between kinase and inhibitor, molecular dynamics simulation can be used to study the mechanism of selective kinase inhibition. And molecular dynamics simulation has been widely applied for the research of selective kinase inhibition.Dihydropyrimidinones and spiro heterocyclic substituted indole compounds have a broad spectrum of biological and pharmacological properties. They can be used as the anticancer agents, anti-microbial drugs, and etc.. Therefore, the syntheses of dihydropyrimidinones and spiro heterocyclic substituted indole compounds through Biginelli reaction have gained great interest in organic synthesis and medicinal chemistry.In this paper, the main work is about the design, syntheses, bioactivity test, modeling studies of the PKB inhibitors and Biginelli reaction. The contents are listed as the following:(1)、MD simulations were performed on the nine complexes of PKA, PKBa, and PKBa in silico mutants, with pyrrolopyrimidine inhibitors. Based on the analyses of the different binding modes of pyrrolopyrimidine inhibitors with different kinases, reasonable explanations were proposed for the mechanism of the selectivity of PKBa inhibitors for PKBa over PKA according to MD simulation studies. The MD results were consistent with the experimental data. Some rules for the structural modifications of PKB inhibitors were also proposed to guide the design of PKB-selective inhibitors over PKA.(2)、MD simulations were performed on the seven complexes of PKBa and ROCK1with pryridine inhibitors. Based on the analyses of the different binding modes of pyridine inhibitors with different proteins, reasonable explanations were given for the mechanism of the selectivity of PKBa inhibitors for PKBa over ROCK1according to MD simulation studies. The MD results were consistent with the experimental data. Some rules for the structural modifications of PKB inhibitors were also proposed to guide the design of PKB-selective inhibitors over ROCK1.(3)、MD simulations were performed on the three complexes of PKBa with different allosteric inhibitors. Reasonable explanations were given for the binding mode and inhibitory mechanism of allosteric inhibitor according to MD simulations studies. The MD results were consistent with the experimental data. Some rules for the structural modifications of inhibitors were also proposed to guide the design of PKB allosteric inhibitors.(4).3D-QSAR models for both CoMFA and CoMSIA were generated to highlight the structural requirements for PKBa inhibition. MD simulations were performed on the five complexes of PKB subtypes with ATP-independent inhibitors. Reasonable explanations were given for the binding mode and PKBa-selective inhibitory mechanism of ATP-independent inhibitor according to MD simulations studies. The obtained results were consistent with the experimental data. Combining with the3D-QSAR results of ATP-independent inhibitors, some rules for the structural modifications of inhibitors were also proposed to guide the design of PKB ATP-independent inhibitors.(5)、MD simulations were performed on the three complexes of PKBa with different peptide inhibitors. Reasonable explanations were given for the binding mode of peptide pseudosubstrate inhibitor according to MD simulations studies. The obtained results were consistent with the experimental data. Some rules for the structural modifications of inhibitors were also proposed to guide the design of PKB pseudosubstrate inhibitor.(6)、Combining with the results from molecular modeling and the experitments, we mainly designed nine kinds of PKB inhibitors. And89compounds were synthesized in this paper.51compounds were carried out with in vitro inhibition assays against PKBa. The in vitro inhibition assays against PKBa of other compounds will be further carried out.(7)、The Lu(OTf)3-catalyzed and chloro(chloromethyl)dimethylsilane (CMDMCS)-mediated Biginelli reactions were investigated in this paper. The aldehydes/isatins/acetal,1,3-dicarbonyl compounds/ketal, and urea/thiourea were taken as the strarting materials to obtain22different dihydropyrimidinone compounds with high yields. The experiments have achieved good results. Lu(OTf)3can be recycled and reused, and CMDMCS is cheap and available. Therefore, Lu(OTf)3and CMDMCS provided new ways to sythesize dihydropyrimidinone compounds, which laid a foundation for the further research of these compounds.