Synthesis, biophysical analysis and biological evaluation of tricyclic pyrones and pyridinones as anti-alzheimer agents

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dc.contributor.author Rana, Sandeep
dc.date.accessioned 2009-10-01T18:36:03Z
dc.date.available 2009-10-01T18:36:03Z
dc.date.issued 2009-10-01T18:36:03Z
dc.identifier.uri http://hdl.handle.net/2097/1732
dc.description.abstract The objectives of this research project were to (i) synthesize different bicyclic and tricyclic pyrone and pyridinone compounds; (ii) study the mechanism of action of these compounds in solution as anti-Aβ (amyloid β) agents using different biophysical techniques; and (iii) study the biological activity of pyrone compounds for the counteraction of Aβ toxicity using MC65 cells, a human neuroblastoma cell line and 5X- familial Alzheimer’s disease (5X FAD, a transgenic mice with five different mutations) mice. A series of tricyclic pyrone and pyridinone compounds were investigated. The tricyclic pyrones and pyridinones were synthesized utilizing a condensation reaction between cyclohexenecarboxaldehye (25) and 4-hydroxy-6-methyl-2-pyone (24) or 4-hydroxy-6-methyl-2-pyridinone (51), respectively. A tricylic pyrone molecule CP2 (2, code name) was synthesized and has an adenine base unit attached to the pyrone core. For structure activity relationship (SAR) studies, the adenine group of CP2 was replaced with other DNA base units (thymine, cytosine and guanine) and various heterocyclic moieties. Since nitrogen containing compounds often exhibit increased bioactivity and brain-penetrating abilities, oxygen atom (O5’) was displaced with a nitrogen atom in the middle ring of the tricyclic pyrone. A condensation reaction of pyrone 51 and 25 was carried out to give the linear pyranoquinoline (52) and the L-shaped pyranoisoquinoline (53). The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer’s disease (AD). Recent studies suggest that soluble Aβ oligomers rather then protofibrils and fibrils may be the primary toxic species. Different biophysical techniques including atomic force microscopy (AFM), circular dichroism (CD), surface plasmon resonance (SPR) spectroscopy, and protein quantification assays were used to study the mechanism of aggregation of Alzheimer Aβ peptide in solution. In search of potentially bioactive compounds for AD therapies, MC65 cell line was used as a screening model. Different tricyclic pyrone and pyridinone compounds protect MC65 cells from death. We studied the efficacy of CP2 in vivo by treatment of 5X FAD mice, a robust Aβ42-producing animal model of AD, with a 2-week course of CP2, which resulted in 40% and 50% decreases in non-fibrillar and fibrillar Aβ species respectively. en_US
dc.language.iso en_US en_US
dc.publisher Kansas State University en
dc.subject Anti-Alzheimer agents en_US
dc.subject Tricyclic pyrone en_US
dc.subject Tricyclic pyridinone en_US
dc.subject Atomic force microscopy en_US
dc.subject MC65 cells en_US
dc.subject In vivo studies en_US
dc.title Synthesis, biophysical analysis and biological evaluation of tricyclic pyrones and pyridinones as anti-alzheimer agents en_US
dc.type Dissertation en_US
dc.description.degree Doctor of Philosophy en_US
dc.description.level Doctoral en_US
dc.description.department Department of Chemistry en_US
dc.description.advisor Duy H. Hua en_US
dc.subject.umi Chemistry, Biochemistry (0487) en_US
dc.subject.umi Chemistry, Organic (0490) en_US
dc.subject.umi Chemistry, Pharmaceutical (0491) en_US
dc.date.published 2009 en_US
dc.date.graduationmonth December en_US


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