Antioxidant small molecules aimed at targeting metal-based oxidative stress in neurogenerative disorders
Inventors
Green, Kayla Nalynn • Lincoln, Kimberly Marie • Gonzalez, Paulina
Assignees
Publication Number
US-8969549-B2
Publication Date
2015-03-03
Expiration Date
2033-12-13
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Abstract
Amine chelates capable of antioxidant capacity and amyloid disaggregation are shown which may be useful in targeting metal-based oxidative stress in neurodegenerative disorders. Pyclen, a backbone commonly investigated for contrast agent imaging, may be repurposed as an anti-oxidant chelator for disaggregating amyloid. The antioxidant capacity of pyclen is enhanced dramatically via conversion of the pyridine backbone to a pyridol with cellular studies showing superior antioxidant capacity while retaining chelation ability to protect amyloid from metal ions aggregation and also disaggregate amyloid aggregates. Another family of molecules based upon hybrid heterocyclic amine ligands is also presented.
Core Innovation
The invention provides amine chelates, specifically designed as antioxidant small molecules, which possess both antioxidant capacity and the ability to disaggregate amyloid aggregates. These molecules, including pyclen and its derivatives, are intended for targeting metal-based oxidative stress implicated in neurodegenerative disorders such as Alzheimer's disease. The invention addresses the misregulation of metal ions, which contributes to reactive oxygen species (ROS) production and amyloid plaque formation, leading to neurological degradation.
A key aspect of the invention is the modification of the pyclen backbone, a structure commonly used for contrast agent imaging, by converting the pyridine ring to a pyridol ring. This chemical modification enhances the molecule's antioxidant activity significantly, as demonstrated in cellular studies, while retaining its chelation abilities. The molecules can protect amyloid from metal-ion induced aggregation and can also disaggregate already formed amyloid aggregates, indicating a dual protective and therapeutic role.
Additionally, the patent describes a family of hybrid heterocyclic amine ligands. These compounds are designed to act as ligands that can rescue copper misplaced in amyloid plaques and restore solubility, as well as quench radicals generated by oxygen-based species to reduce neuronal damage. The invention deliberately targets the regulation of metal-ion association with amyloid and the neutralization of ROS in order to address the lack of effective or preventative protocols for neurodegenerative decline linked to metal-based oxidative stress.
Claims Coverage
The independent claim covers a molecule selected from a specific group consisting of defined chemical structures with dual antioxidant and chelating properties.
Molecule with combined antioxidant capacity and amyloid disaggregation
A molecule selected from the group consisting of: - Pyclen and its derivatives, including variants where the pyridine ring is converted to a pyridol. - Hybrid heterocyclic amine ligands constructed to function as both potent antioxidants and chelators for metal ions. These molecules are characterized by: - The ability to chelate transition metal ions such as copper(II) and zinc(II) with specific log K constants. - The demonstrated capacity to prevent or reverse amyloid aggregation induced by metal ions. - Enhanced antioxidant activity as shown in radical scavenging assays and in cellular studies indicating protection against oxidative stress.
The inventive features protect a new class of small molecules with both antioxidant and chelating functionalities, engineered for prevention and disruption of metal-induced amyloid aggregation and reduction of metal-based oxidative stress in neurodegenerative contexts.
Stated Advantages
Pyclen and its derivatives show superior antioxidant capacity while retaining the ability to chelate metals and protect or disaggregate amyloid aggregates.
The molecules can enter cells without interrupting vital cytosolic metalloenzyme functions.
Enhanced antioxidant activity is achieved by chemical modification (pyridine to pyridol conversion) of the molecular backbone.
Hybrid heterocyclic amines offer both the restoration of metal-ion homeostasis and the quenching of radicals in neuronal environments.
Documented Applications
Targeting metal-based oxidative stress in neurodegenerative disorders, including Alzheimer's disease, Huntington's, Parkinson's, Lou Gehrig's disease, macular degeneration, and Friedreich's ataxia.
Prevention and disaggregation of beta-amyloid plaques associated with Alzheimer's disease.
Cellular protection against oxidative stress through antioxidant activity in models such as FRDA fibroblasts and neuronal cell lines.
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