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

Institute of Organic and Medicinal Chemistry, University of Pécs, Szigeti st 12, H-7624 Pécs, Hungary.
European Journal of Medicinal Chemistry (Impact Factor: 3.45). 02/2011; 46(4):1348-55. DOI: 10.1016/j.ejmech.2011.01.059
Source: PubMed


A series of 2-aminofluorenes N-alkylated with nitroxides or their precursors were synthesized. The new compounds were tested on hydroxyl radical and peroxyl radical scavenging ability and inflammatory assay on the endothelial brain cells. In agreement with ROS scavenging ability the same compound 7-bromo-N -[(1-Oxyl-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine-4yl)methyl]-9H-fluoren-2-amine (3b) and its hydroxylamine salt (3b/OH/HCl) showed the anti-inflammatory property on the endothelial brain cells.

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Available from: John C Voss, Jun 16, 2014
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    • "It was recently shown that unfolded protein response and ATF3 are associated with inflammation response related to atherosclerosis in endothelial cells [49,50]. Our previous studies have shown that TGRL lipolysis products activate stress response pathways that induce expression of multiple pro-inflammatory and pro-apoptotic genes leading to endothelial dysfunction [5,51]. "
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    ABSTRACT: Background Neurovascular inflammation is associated with a number of neurological diseases including vascular dementia and Alzheimer’s disease, which are increasingly important causes of morbidity and mortality around the world. Lipotoxicity is a metabolic disorder that results from accumulation of lipids, particularly fatty acids, in non-adipose tissue leading to cellular dysfunction, lipid droplet formation, and cell death. Results Our studies indicate for the first time that the neurovascular circulation also can manifest lipotoxicity, which could have major effects on cognitive function. The penetration of integrative systems biology approaches is limited in this area of research, which reduces our capacity to gain an objective insight into the signal transduction and regulation dynamics at a systems level. To address this question, we treated human microvascular endothelial cells with triglyceride-rich lipoprotein (TGRL) lipolysis products and then we used genome-wide transcriptional profiling to obtain transcript abundances over four conditions. We then identified regulatory genes and their targets that have been differentially expressed through analysis of the datasets with various statistical methods. We created a functional gene network by exploiting co-expression observations through a guilt-by-association assumption. Concomitantly, we used various network inference algorithms to identify putative regulatory interactions and we integrated all predictions to construct a consensus gene regulatory network that is TGRL lipolysis product specific. Conclusion System biology analysis has led to the validation of putative lipid-related targets and the discovery of several genes that may be implicated in lipotoxic-related brain microvascular endothelial cell responses. Here, we report that activating transcription factors 3 (ATF3) is a principal regulator of TGRL lipolysis products-induced gene expression in human brain microvascular endothelial cell.
    Full-text · Article · Jul 2014 · BMC Systems Biology
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    • "We have recently published the structure of spin-labeled fluorene (SLF), containing a pyrroline nitroxide group that provides both increased cell protection against toxicity of Ab oligomers (AbO) and a route to directly observe the binding of the fluorene to the AbO assembly by EPR spectroscopy [10]. Among the fluorene derivatives , the pyrroline nitroxide ring-containing derivatives were found especially useful in counteracting Ab peptide toxicity, as they posses both antioxidant properties and the ability to disrupt AbO species [10]. "
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    ABSTRACT: A series of new Tacrine analogs modified with nitroxides or pre-nitroxides on 9-amino group via methylene or piperazine spacers were synthesized; the nitroxide or its precursors were incorporated into the Tacrine scaffold. The new compounds were tested for their hydroxyl radical and peroxyl radical scavenging ability, acetylcholinesterase inhibitor activity and protection against Aβ-induced cytotoxicity. Based on these assays, we conclude that Tacrine analogs connected to five and six-membered nitroxides via piperazine spacers (9b, 9b/HCl and 12) exhibited the best activity, providing direction for further development of additional candidates with dual functionality (anti Alzheimer's and antioxidant).
    Full-text · Article · Apr 2014 · European Journal of Medicinal Chemistry
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    • "Potency of SLF compounds [15] against Aβ toxicity as determined by the MTT assay. "
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    ABSTRACT: The 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. To 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. Fluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they possess both antioxidant properties and the ability to disrupt AβO species.
    Full-text · Article · Apr 2012 · PLoS ONE
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