Antioxidant small molecules aimed at targeting metal-based oxidative stress in neurodegenerative disorders
Inventors
Green, Kayla Nalynn • Lincoln, Kimberly Marie • Gonzalez, Paulina
Assignees
Publication Number
US-8969548-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 was 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.
Core Innovation
The invention relates to the development of potent biomodal antioxidant small molecules that are capable of beta-amyloid prevention and disaggregation, specifically for targeting metal-based oxidative stress in neurodegenerative disorders such as Alzheimer’s disease. The misregulation of metal ions, particularly transition metals like copper and zinc, is known to produce reactive oxygen species (ROS) which lead to neurological degradation and facilitate the formation of beta-amyloid (Aβ) plaques. Existing chelator therapies have faced limitations such as ion specificity, inability to cross the blood-brain barrier, and biological compatibility.
This invention repurposes pyclen, previously utilized as a backbone for contrast agent imaging, as a metal-chelating antioxidant capable of disaggregating amyloid plaques. Studies demonstrated that pyclen and its derivatives can both protect amyloid from metal-induced aggregation and promote disaggregation of amyloid aggregates. The antioxidant activity originates from the pyridine backbone, and further enhancement is achieved by converting the pyridine to a pyridol ring, resulting in superior antioxidant capacity.
Cellular and in vitro assays confirm that both the original and modified compounds exhibit antioxidant action, significant cell compatibility, and the dual function of metal sequestration and amyloid disaggregation. This bimodal approach of modulating both metal ion-induced amyloid aggregation and associated oxidative stress addresses the underlying issues observed in neurodegenerative disorders, providing a strategy for therapeutic intervention where previous chelator designs were insufficient.
Claims Coverage
The patent contains at least one independent claim focused on the design and application of specific small molecule structures with antioxidant and chelating properties targeting metal-based oxidative stress and amyloid aggregation.
Molecule having the structural formula
The invention covers a molecule characterized by a specific structural formula as claimed. - The molecule is an amine chelate derived from a pyclen backbone. - It has both antioxidant capacity and the ability to disaggregate amyloid, while protecting against metal-ion induced amyloid aggregation. - The antioxidant property can be dramatically enhanced by converting the pyridine backbone of pyclen to a pyridol, forming a modified molecule with superior antioxidant capability while retaining metal chelation. - The molecule acts bimodally by both chelating transition metals that bind to amyloid and by attenuating reactive oxygen species generated by these metals.
The claims are directed to a structurally-defined chelating molecule with bimodal activities: metal-ion chelation to inhibit amyloid aggregation, and antioxidant functionality that can be enhanced through chemical modification of the molecule’s core.
Stated Advantages
The molecules provide bimodal modulation by chelating metal ions involved in amyloid aggregation and regulating increased levels of reactive oxygen species associated with neurodegenerative disorders.
The pyclen-based molecules exhibit superior antioxidant capacity compared to existing chelators and retain their ability to prevent and disaggregate amyloid aggregates.
Conversion of the pyridine backbone to a pyridol further enhances antioxidant capacity while preserving metal-ion chelation, providing improved therapeutic potential.
The compounds demonstrate cellular compatibility, effectively protect against oxidative stress, and do not interrupt vital functions of cytosolic metalloenzymes.
Documented Applications
Targeting metal-based oxidative stress in neurodegenerative disorders, specifically in the context of Alzheimer’s disease.
Prevention and disaggregation of beta-amyloid plaques through metal ion chelation.
Therapeutic intervention in disorders characterized by increased oxidative stress and abnormal metal ion homeostasis, such as Huntington's, Parkinson's, Lou Gehrig's disease, macular degeneration, and Friedreich's ataxia.
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