Department of ChemistryAlzheimer???s disease (AD) is most common form of dementia. Symptomatically, memory loss and cognitive decline is observed. In 2016, more than 33 million people worldwide are suffered from AD. The complexity of AD, however, stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. For example, the amyloid-?? (A??) peptides aggregate toward bigger species and form the senile plaque in AD brain. The high concentration of metal ions [e.g., Cu(I/II), Zn(II), and Fe(II/III)] are observed in this senile plaques. Metal ions also could bind to A?? and show different properties with metal-free A??. Additionally, from these redox active metal ions [e.g., Cu(I/II) and Fe(II/III)], could overproduce the reactive oxygen species (ROS) through Fenton-like reactions. To identify the involvement of metal-bound amyloid-?? (metal???A??) aggregation in AD pathology, small molecules as chemical tools capable of controlling metal???A?? aggregation have been developed. Herein, we describe the design of small molecules as chemical tools to target metal???A??. Introduction of hypotheses of the AD and previous reported chemical tools for metal???A?? in Chapter 1, and 2,2???-bipyridine (bpy) derivatives (1???4) rationally designed to be chemical modulators towards metal???A??? aggregation over metal-free A?? analog will be described in Chapter 2. Additionally, design molecule to inhibit the transcription factor, ??FosB are proposed in Appendix A. Overall, our studies of the bpy derivatives demonstrate that the alteration of metal binding properties as well as the installation of an A?? interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal???A?? aggregation. Obviating the need for complicated structures, our design approach could be appropriately utilized for inventing small molecules as chemical tools for studying desired metal-related targets in biological systems.ope
