Metal containing enzymes play a crucial role in protecting cells from reactive oxygen species (ROS). These types of enzymes may function as antioxidants and are essential to the human body as oxidative stress can be damaging to cells thus having implications with anticancer and anti aging mechanisms. Biomimetic modeling is a way to study these enzymes by making synthetic analogues of the enzyme’s active site. Such studies are integral to understanding the enzyme’s functionality and mechanism of action. The focus of this investigation is Cu,Zn superoxide dismutase (SOD1), an enzyme responsible for scavenging the toxic superoxide radical produced during aberrant metabolism by catalyzing the dismutation of superoxide into molecular oxygen and hydrogen peroxide. Recent findings suggest aggregation of the copper sub-unit can cause the protein to act as an aberrant form of SOD1, which can be linked to neurodegenerative diseases such as familial amyotrophic lateral sclerosis (fALS). Notably, the electrostatic loop (ESL) of SOD1, a conserved cluster of charged residues, is said to be associated with the mobility of the copper binding site. More specifically, the ESL functions as a “breathing motion” for the binding site which allows for proper catalytic functionality by alternating structural conformations intermediate between planar Cu(I) and tetrahedral Cu(II) oxidation states. Loss of ESL mobility can cause the Cu center to be stranded in a distorted geometry which may catalyze the binding of hydrogen peroxide to then lead to the activation of fenton-type chemistry associated with aberrant behavior. To investigate these ideas, this work will introduce the synthesis and characterization of pyridine based N4-copper(II) and copper (I) complexes in order to mimic the redox activity and structural properties of the native and aberrant copper binding site in SOD1. Their reactivity towards SOD relevant oxidants such as hydrogen peroxide, alkyl peroxides and molecular oxygen will be discussed.

Investigating the redox behavior of pyridine based copper (II) and copper(I) complexes which structurally mimic the binding site of Cu, Zn superoxide dismutase (SOD1)

ACS Spring Meeting 2021

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