碩士 / 長庚大學 / 中醫學系天然藥物 / 105 / Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder, and it’s the most common disease cause of dementia in the elderly people. The amyloid hypothesis supposed that amyloid beta (Aβ) deposits are the key cause of the disease, and metal ions such as copper (II) and zinc (II) have been playing a role in the aggregation and toxicity of the Aβ peptide. Moreover, inflammation is also a pathological feature of Alzheimer's disease. Previous studies had shown that neutrophils infiltrate brain is associated with neurodegenerative diseases. In addition, the concentration of SIRT 2 also play a role in the pathogenesis of Alzheimer disease. Analysis of X-ray data demonstrated that sirtinol is a metal ions chelating agent, which can bind metal cations (eg, copper, zinc and iron) in a 1:1 ratio. Previous studies also had shown that sirtinol significantly inhibits HNE activity in N-formyl-methionyl-leucyl-phenylalanine (fMLF)-activated human neutrophils, and it also inhibit human SIRT 2, thus sirtinol was selected as a lead compound herein. Twenty seven sirtinol derivatives were synthesized and evaluated their inhibitory effects on HNE and SIRT 2 activity, and chelating effect on metal ion. The results showed that increasing carbon chain of sirtinol or replacing benzenyl group with cyclohexane will cause less active products. Additionally modification of the imine group of sirtinol to amine or azo groups are unfavorable to inhibit HNE but improved the stability. Moreover, replacing methyl group of sirtinol with ester group or carboxylic acid group, the water solubility were improved. In addition, compounds with carboxylic acid group have better inhibition activity, and replaced with pyridine ring exhibited potent effect. At the same time, we found the 2-hydroxy-1-napthol group of sirtinol is very important for inhibiting HNE activity. By the analysis of structure-activity relationships (SARs) and modification with isosteres theory, we found JYLRX21 exhibited better activity (HNE and SIRT 2) than sirtinol. Furthermore, the data demonstrated that JYLRX21 have interaction with copper ions. After all, JYLRX21 is a potential compound to modulate multiple Facets of Alzheimer’s disease.
| Identifer | oai:union.ndltd.org:TW/105CGU05553008 |
| Date | January 2017 |
| Creators | Jing Yi Lin, 林靖倚 |
| Contributors | P. W. Hsieh, 謝珮文 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 251 |
Page generated in 0.0014 seconds