Synthesis and study of 2-amino-7-bromofluorenes modified with nitroxides and their precursors as dual anti-amyloid and antioxidant active compounds

Kálai, Tamás; Petrlová, Jitka; Balog, Mária; Aung, Hnin Hnin; Voss, John C.; Hideg, Kálmán

doi:10.1016/j.ejmech.2011.01.059

Cited by 15 publications

(17 citation statements)

References 31 publications

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“…As mentioned above, HO-4160 is one of a group of related SLF compounds that we have recently described [15]. We also measured the ability of the other related SLF analogs (see Fig.…”

Section: Resultsmentioning

confidence: 99%

The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide

et al. 2012

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BackgroundThe deposition and oligomerization of amyloid β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). Aβ peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by β and γ secretases. Several lines of evidence point to the soluble Aβ oligomer (AβO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the AβO species.Methodology/Principal FindingsTo achieve a better understanding of the mechanism of action of this disruptive ability, we extend the application of electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels in the Aβ peptide to investigate the binding and influence of fluorene compounds on AβO structure and dynamics. In addition, we have synthesized a spin-labeled fluorene (SLF) containing a pyrroline nitroxide group that provides both increased cell protection against AβO toxicity and a route to directly observe the binding of the fluorene to the AβO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block AβO toxicity, scavenge free radicals and diminish the formation of intracellular AβO species.ConclusionsFluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they posses both antioxidant properties and the ability to disrupt AβO species.

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“…As mentioned above, HO-4160 is one of a group of related SLF compounds that we have recently described [15]. We also measured the ability of the other related SLF analogs (see Fig.…”

Section: Resultsmentioning

confidence: 99%

The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide

et al. 2012

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“…We have identified fluorene compounds, based on a highly rigid tricyclic fluorene ring originally developed as potential PET and SPECT imaging agents, on the basis of their amyloid affinity and blood brain barrier permeability [19], that are able to permeate cells, inhibit Aβ aggregation and neutralize the toxicity of soluble AβO [20]. More recently, we have synthesized bi-functional fluorenes by attaching nitroxides to the fluorene compound (Figure 1) [21]. We found the protective effect of these spin-labeled fluorenes (SLFs) is superior to the fluorene template and derives from the targeted antioxidant activity of the compound’s nitroxide moiety [22].…”

Section: Introductionmentioning

confidence: 99%

Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure

Altman

Hilt

et al. 2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Alzheimer’s disease is characterized by the presence of extracellular plaques comprised of amyloid beta (Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer’s disease. Single particle analyses of Aβ oligomers in solution by fluorescence correlation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenes (SLFs; bi-functional small molecules that block the toxicity of Aβ) prevent and disrupt oligomeric assemblies of Aβ in solution. Furthermore, the circular dichroism (CD) spectrum of untreated Aβ shows a continuous, progressive change over a 24-hour period, while the spectrum of Aβ treated with SLF remains relatively constant following initial incubation. These findings suggest the conformation of Aβ within the oligomer provides a complementary determinant of Aβ toxicity in addition to oligomer growth and size. Although SLF does not produce a dominant state of secondary structure in Aβ, it does induce a net reduction in beta secondary content compared to untreated samples of Aβ. The FCS results, combined with electron paramagnetic resonance spectroscopy and CD spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers, while retaining Aβ as a population of smaller, yet largely disordered oligomers.

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“…IRDye ® 680RD Goat (polyclonal) anti-mouse IgG (H+L) highly cross absorbed, excitation wavelength 676 nm, emission wavelength 694 nm (LI-COR GmbH, Germany). Spin-labeled fluorene HO-4160 (7-Bromo- N —[(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl]-9H-fluoren-2-amine radical) was synthesized as previously described [29]. Hexafluoro-iso-propanol (HFIP) was purchased from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

A Metal-Free Method for Producing MRI Contrast at Amyloid-β

Hilt

Tang

Walton

et al. 2016

JAD

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Alzheimer’s disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of SLF into live mice resulted in good brain penetration, with the compound able to generate contrast 24-hr post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by magnetic resonance imaging (MRI).

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Synthesis and study of 2-amino-7-bromofluorenes modified with nitroxides and their precursors as dual anti-amyloid and antioxidant active compounds

Cited by 15 publications

References 31 publications

The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide

The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide

Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure

A Metal-Free Method for Producing MRI Contrast at Amyloid-β

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