Copper enzymes that react with dioxygen are essential to our lives especially with respect to transforming certain biological molecules from one form to another. Yet, in areas of high metabolic activity such as the brain, mismanagement of copper resources is thought to lead to many debilitating diseases including Alzheimer's (AD) and Parkinsons. The hallmark of these diseases is the formation of plaques with misfolded protein fragments that are often damaged by oxidization. Defining the ligation environment and the mechanism by which adventitiously bonded or purposely sequestered copper is able to create reactive dioxygen species (ROS) is what we endeavor to understand. As copper is the most labile of all redox active metals in biology, defining the coordination that leads to such ROS is challenging. Mechanisms of the reaction of copper with dioxygen in highly controlled coordination environments, such as proteins or in small copper complex, provides a logical start to define what is chemically possible or if not what is chemically probable under less-defined biological conditions. The broad and long-term objectives are how to attenuate the formation of ROS at copper sites that activate dioxygen through an understanding of the mechanism of activation. More specifically, copper sites that activate O2 in the presence of phenolates/phenols groups will be investigated at depth as such sites have been implicated as ROS generators in plaques associated with AD. The synthetic analog approach will be our investigation tool whereby structurally-related low molecular weight complexes will be synthesized and examined at a small molecule level of detail to reveal intrinsic structural, electronic, and reactivity properties uncoupled from the influences of the protein matrix. The operating premise is that such complexes will provide important mechanistic insights to the oxidative (CuI + O2 ) and reductive (Cu-O2 + substrate) half-reactions of biological systems if appropriate attention is directed to creating appropriate copper ligation environments. Particular attention will be focused on the most highly oxidized form(s) copper and how different electronic distributions lead to different reactivity. PUBLIC HEALTH RELEVANCE: Copper enzymes that react with dioxygen are essential to our lives especially with respect to transforming certain biological molecules from one form to another. A number of prominent neurological diseases including Alzheimer's disease are thought to result from a mismanagement of these copper resources and, under the conditions of oxidative stress create, reactive oxygen species (ROS) that lead to irreversible damage of nerve cells and dementia. Our research attempts to define how copper is held by proteins that create these damaging ROS with an eye toward developing appropriate copper binding agents that might attenuate ROS production and the progression of these debilitating diseases.