Development of Small Molecules as Modulators of Amyloidogenic Peptides Associated with Alzheimer’s Disease and Type II Diabetes Mellitus

Abstract

The progressive degenerative disorders, Alzheimer’s disease (AD) and type II diabetes mellitus (T2DM), are characterized by the accumulation of misfolded peptides [i.e., amyloid-b (Ab) and human islet amyloid polypeptide (hIAPP), respectively]. In addition, multiple factors, such as metal ions and reactive oxygen species (ROS), are shown to be interconnected and involved in these peptides’ aggregation and toxicity. The inter-relationship between Ab or hIAPP, metals, ROS, and toxicity is not clear, however. In order to gain a better understanding of this interconnection, chemical tools capable of targeting metal-associated peptides and modulating their reactivities (i.e., peptide aggregation, metal-peptide-induced ROS formation) have been developed. In Chapters 2 and 3, the investigations, including cytotoxicity, regulatory activity toward Ab-/metal Ab-induced toxicity, and antioxidant activity, of small molecules, designed to target metal-Ab and control their reactivities, are described. Moreover, the initial studies of metal influence on hIAPP’s toxicity in living cells are discussed in Chapter 4. Overall, the overall studies in this thesis have provided insight into designing new chemical tools used for investigating multiple facets in AD and T2DM.