Session: Current Topics in Biological Chemistry:

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by amyloid-beta plaques, tau tangles, and unregulated reactive oxygen species (ROS). The production of ROS in the brain is exacerbated by an excess of free-metal ions in nervous tissue. Tetra-azamacrocycles have been shown by this group and others to have the ability to scavenge free-metal ions and quench ROS. These macrocyclic ligands have, thus, been considered as therapeutic agents for combatting AD. The ability of a neuro-active pharmaceutical to cross the blood-brain barrier (BBB) is crucial to its pharmacological success. The aim of this work is to enhance the pharmacological potential of these macrocyclic ligands. To accomplish this, computational analyses were performed on two tetra-azamacrocycles to predict their baseline BBB permeability. The structures of these macrocycles were then modified with various moieties and analyzed via the same computational methods to predict their BBB permeability potential. The target of this project is focused on is the attachment of antioxidant molecules to these tetra-azamacrocycles. Antioxidant moieties have beneficial anti-inflammatory properties and many have the potential to be transported across the blood-brain barrier. Thus, these moieties are an attractive option for enhancing the pharmacological potential of the Green Group macrocyclic ligands. To accomplish the attachment of antioxidant appendages, the synthetic approach of one of the Green Group’s flagship tetra-azamacrocycles, ^OHPy-N₃, had to be completely reimagined. New synthetic approaches and protection strategies were employed to achieve a suitable intermediate primed for the addition BBB permeability enhancing antioxidants. These novel synthetic methods and subsequent results are discussed in this work herein.

Kristof Pota

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