Bifunctional Modulators of Abeta Aggregation as Potential Agents for Alzheimer's Disease Therapy
| Autor: | Li-Hsin Hsu, 許儷馨 |
|---|---|
| Rok vydání: | 2013 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 101 One hundred years after discovery of Alzheimer’s disease (AD), various studies have been providing evidence that metal ions are critically involved in the pathogenesis of it. Transition metals, including copper and zinc, have been found in amyloid plaques at high level. These metal ions led to the formation of reactive oxygen species (ROS), which can further induce neurodegeneration and be one proposed neuropathology of AD. Metal chelator is one of the potential therapeutics for AD. One of the well-known chelators, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQ) has been shown to improve cognition in the phase II clinical trials. However, most chelators cannot cross the blood brain barrier (BBB). Due to lack of Aβ recognition, these chelators do not specifically bind to metal ions in Aβ without removing vital metal from other biological system. Here, we focused on the incorporation of chelation moiety of clioquinol into p-125I-stilbene framework (Aβ imaging agent) to build bifunctional metal chelators. HLH2 and HLH4 were prepared by using this strategy. By using the UV- Vis spectroscopy, we found that HLH2 and HLH4 can chelate copper or zinc ion effectively. In inhibition test, both compound 1 and HLH2 were equal potency in decreasing Cu2+ or Zn2+-induced Aβ42 aggregation. In decreasing Aβ42 aggregation of disaggregation test, HLH2 was 1.25 fold more potency than 1. The study demonstrated that HLH2 could be the leading structure of the novel therapy for AD. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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