An N-Heterocyclic Amine Chelate Capable of Antioxidant Capacity and Amyloid Disaggregation

Lincoln, Kimberly M.; Richardson, Timothy E.; Rutter, Lauren A.; González, Paulina; Simpkins, James W.; Green, Kayla N.

doi:10.1021/cn300060v

Cited by 52 publications

(53 citation statements)

References 82 publications

(169 reference statements)

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“…Several bio-metals, especially the redox-active Cu 2+ , are involved in oxidative stress, which triggers neuronal cell death as seen in AD 31 51 . To evaluate the ability of the target compounds to halt the copper redox cycling via metal complexation under aerobic conditions, the Cu-ascorbate redox system was used as a model ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

Zhang

Xie

et al. 2016

Sci Rep

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Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

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Section: Resultsmentioning

confidence: 99%

Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

Zhang

Xie

et al. 2016

Sci Rep

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“…For example, the aggregation of beta-amyloid, that is associated with the origins of Alzheimer's disease, is accelerated by copper and zinc ions, which are also found on autopsy at abnormally high concentrations (~ mM) in neuro senile plaques and fibrils [1]. Therapies capable of inhibiting and reversing this aggregation are the subject of global research [2].…”

Section: Introductionmentioning

confidence: 99%

Metal ion influence on eumelanin fluorescence and structure

Sutter¹,

Birch²

2014

Methods Appl. Fluoresc.

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Melanin has long been thought to have an unworkably weak and complex fluorescence, but here we study its intrinsic fluorescence in order to demonstrate how metal ions can be used to control the rate of formation, constituents and structure of eumelanin formed from the well-known laboratory auto-oxidation of 3, 4-dihydroxy-L-phenylalanine (L-DOPA). The effect on eumelanin absorption and fluorescence of a range of solvated metal ions is reported including Cu, Zn, Ni, Na and K. Monovalent cations and Zn have little effect, but the effect of transition metal cations can be considerable. For example, at pH 10, copper ions are shown to accelerate the onset of eumelanin formation, but not the rate of formation once it commences, and simplify the usual complex structure and intrinsic fluorescence of eumelanin in a way that is consistent with an increased abundance of 5,5-dihydroxyindole-2-carboxylic acid (DHICA). The presence of a dominant 6 ns fluorescence decay time at 480 nm, when excited at 450 nm describes a distinct photophysically species, which we tentatively assign to small oligomers. Copper is well-known to normally quench fluorescence, but increasing amounts of copper surprisingly leads to an increase in the fluorescence decay time of eumelanin, while reducing the fluorescence intensity, suggesting copper modification of the excited state. Such results have bearing on diverse areas. The most accepted morphology for melanin is that of a graphite-like sheet structure, and one which readily binds metal ions, an interaction that is thought to have an important, though as yet unclear bearing on several areas of medicine including neurology. There is also increasing interest in bio-mimicry by preparing and labelling sheet structures with metal ions for new electronic and photonic materials.

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“…5, 12, 14, 17 Given this success we set-out to enhance the antioxidant activity of 1 , without affecting the metal ion chelation capability. 18, 19 The conversion from a pyridine to a pyridol, ( 2 ) was pursued as pyridols are known to react with hydroxyl radicals via addition at the C3 or C5 position of the pyridol ring with the products being reminiscent of tannins, well known for their antioxidant power.…”

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confidence: 99%

A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders

Lincoln

González²,

Richardson³

et al. 2013

Chem. Commun.

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Metal-ion misregulation and oxidative stress have been linked to the progressive neurological decline associated with multiple neurodegenerative disorders. Transition metal-mediated oxidation of biomolecules via Fenton chemical reactions plays a role in disease progression. Herein we report the synthesis, characterization and antioxidant activity of 2; a pyclen derivative with enhanced antioxidant character.

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An N-Heterocyclic Amine Chelate Capable of Antioxidant Capacity and Amyloid Disaggregation

Cited by 52 publications

References 82 publications

Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

Metal ion influence on eumelanin fluorescence and structure

A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders

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