Design, Synthesis And Biological Evaluation Of PKB Inhibitors, Galanthamine Derivatives And Synthesis Of Imidazoles And Steroids

The dissertation consists of five chapters. In the first chapter, the current research on PKB and its inhibitors was reviewed. The second chapter described the design and synthesis of a series of PKB inhibitors. The third chapter described the solid phase synthesis of 1,2,5-trisubstituted-4,5-dihydro-lH-imidazole derivatives. In the forth chapter, the design and synthesis of galanthamine derivatives as acetylcholinesterase (AChE) inhibitors was described. In the fifth chapter, one-pot synthesis of 5,9-cyclo-1, 11-oxido-pregn-16-ene-3,20-dione was reported.Protein kinase B(PKB) is a serine/threonine kinase that belongs to the AGC family of kinases. PKB plays a key role in promoting cancer cell proliferation and survival. PKB has become an attractive target for antitumor chemotherapy and inhibitors with different mechanisms targeting PKB pathway have been designed and synthesized recently.In the second chapter, three compound libraries were designed based on the reported structural information of PKB and SARs of PKB inhibitors.77 sulfonamides,10 sulfonamide type of compounds containing amide structure and 15 1,2,4-triazole type of compounds containing biphenyl structure were synthesized in solution. Most of the synthesized compounds have been tested for the biological evaluation in vitro. The data showed that a series of sulfonamides exhibited antiproliferative activities against the selected tumor cell lines and five compounds have more potent cytotoxicity against the selected tumor cell lines compared to the reference compound. While the 1,2,4-triazole type of compounds containing biphenyl structure exhibited lower inhibitory activities against the selected tumor cell lines. The SAR studies demonstrated that the groups in R3, R4 position of sulfonamides were very important for antitumor activity. Several potent compounds have been selected for further PKB inhibitory mechanism investigation.In the third chapter, we report an efficient method to synthesize substituted guanidine compounds 1,2,5- trisubstituted-4,5-dihydro-lH-imidazole derivatives on solid phase from common building blocks, such as amino acids, carboxylic acids and the cyclization reagent N-(dichloromethylene)-N,N-disubstitutedammonium.10 1,2,5-trisubstituted-4,5-dihydro-1H- imidazole derivatives were prepared. The reaction conditions are readily amenable to the synthesis of individual and mixture-based combinatorial libraries.In the forth chapter, the design and synthesis of galanthamine derivatives as AChE inhibitors was described. Alzheimer's disease (AD) is a neurodegenerative disorder, possibably caused by the aggregation and deposition of theβ-amyloid(Aβ) in the brain. Acetylcholinesterase (AChE) inhibitors have been used for AD treatment, by reducing the degradation of acetylcholine and therefore enhancing the acetylcholine concentration in the brain.Galanthamine, a centrally acting competitive and reversible inhibitor, is less potent, but also less toxic and more tolerant than tacrine. In this paper, galanthamine was connetted with another pharmacophore on its D ring through an alkyl linker in order to stimultaneously bind to the catalytic and peripheral sites of acetylcholinesterase and, thereby, provide more potent AChE inhibitors for AD treatment.A new series of galanthamine derivatives have been designed, synthesized and evaluated as acetylcholinesterase inhibitors. All of the new 20 compounds prepared showed high AChE inhibitory activities, especially, compound 40 that has an N-hexyl-benzyl piperidine substituent on the nitrogen atom reaching the best inhibitory activity for AChE (IC50=5.62 nM). The docking study performed with AutoDock demonstrated that 40 was nicely accommodated by AChE.In the fifth chapter, one pot synthesis of 5,9-cyclo-1,11-oxido-pregn-16-ene-3, 20-dione was reported. Treatment of 9-bromide-11-hydroxypregna-1,4,16-trien-3, 20-dione with Raney Ni in absolute ethanol afforded 5,9-cyclo-1, 11-oxido-pregn-16-ene-3,20-dione by two annulation reactions in reasonable yield. The absolute configuration was also confirmed by X-ray crystal analysis.