Rings of Power: Controlling SOD Mimic Activity by the Addition of Pyridine Rings within the Pyridinophane Scaffold

Area of Science:

• Coordination Chemistry
• Bioinorganic Chemistry
• Neuroscience

Background:

• Superoxide dismutase (SOD) enzymes are critical for neutralizing superoxide, a reactive oxygen species implicated in neurodegenerative diseases.
• Dysregulation of reactive oxygen species contributes to neuronal damage and is a hallmark of neurodegenerative conditions.
• Macrocyclic small molecules are being explored as functional mimics of SOD1.

Purpose of the Study:

• To synthesize and characterize a series of tetra-aza macrocyclic PyN ligands with varying pyridine ring substitutions.
• To investigate the impact of these substitutions on the properties of copper(II) complexes (Cu(PyN)) as SOD1 mimics.
• To evaluate the potential of these Cu(PyN) complexes as therapeutic agents for neurological diseases.

Main Methods:

• Ligand characterization using NMR, mass spectrometry, elemental analysis, and potentiometric titrations.
• Copper(II) complex characterization via cyclic voltammetry and X-ray diffraction.
• Evaluation of copper binding affinities (log β) and catalytic activity (kcat).
• Cell toxicity studies in FRDA cells.

Main Results:

• Five tetra-aza macrocyclic PyN ligands with diverse 4-position pyridine substitutions were synthesized and characterized.
• The Cu(PyN) complexes exhibited enhanced binding affinity for Cu(I) without compromising Cu(II) binding.
• The Cu(PyN) series achieved the highest catalytic turnover frequency (kcat = 45.36 M⁻¹ s⁻¹) among reported Cu(II)-based SOD1 mimics.
• Initial toxicity assessments in FRDA cells were conducted.

Conclusions:

• The synthesized PyN ligands and their copper complexes represent highly effective SOD1 mimics.
• These compounds demonstrate superior catalytic activity and favorable metal-binding properties.
• The findings support the further development of these Cu(PyN) complexes as potential therapeutics for neurodegenerative disorders.