Myricetin: A Naturally Occurring Regulator of Metal-Induced Amyloid-β Aggregation and Neurotoxicity

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Recent Development of Bifunctional Small Molecules to Study Metal-Amyloid-β Species in Alzheimer's Disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease related to the deposition of aggregated amyloid-β (Aβ) peptides in the brain. It has been proposed that metal ion dyshomeostasis and miscompartmentalization contribute to AD progression, especially as metal ions (e.g., Cu(II) and Zn(II)) found in Aβ plaques of the diseased brain can bind to Aβ and be linked to aggregation and neurotoxicity. The role of metal ions in AD pathogenesis, however, is uncertain. To accelerate understanding in this area and contribute to therapeutic development, recent efforts to devise suitable chemical reagents that can target metal ions associated with Aβ have been made using rational structure-based design that combines two functions (metal chelation and Aβ interaction) in the same molecule. This paper presents bifunctional compounds developed by two different design strategies (linkage or incorporation) and discusses progress in their applications as chemical tools and/or potential therapeutics

The ongoing search for small molecules to study metal-Associated amyloid-?? species in alzheimers disease

ConspectusThe development of a cure for Alzheimers disease (AD) has been impeded by an inability to pinpoint the root cause of this disorder. Although numerous potential pathological factors have been indicated, acting either individually or mutually, the molecular mechanisms leading to disease onset and progression have not been clear. Amyloid-?? (A??), generated from proteolytic processing of the amyloid precursor protein (APP), and its aggregated forms, particularly oligomers, are suggested as key pathological features in AD-Affected brains. Historically, highly concentrated metals are found colocalized within A?? plaques. Metal binding to A?? (metal-A??) generates/stabilizes potentially toxic A?? oligomers, and produces reactive oxygen species (ROS) in vitro (redox active metal ions; plausible contribution to oxidative stress). Consequently, clarification of the relationship between A??, metal ions, and toxicity, including oxidative stress via metal-A??, can lead to a deeper understanding of AD development.To probe the involvement of metal-A?? in AD pathogenesis, rationally designed and naturally occurring molecules have been examined as chemical tools to target metal-A?? species, modulate the interaction between the metal and A??, and subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands are also capable of attenuating the generation of redox active metal-A??-induced ROS to mitigate oxidative stress. One rational design concept, the incorporation approach, installs a metal binding site into a framework known to interact with A??. This approach affords compounds with the simultaneous ability to chelate metal ions and interact with A??. Natural products capable of A?? interaction have been investigated for their influence on metal-induced A?? aggregation and have inspired the construction of synthetic analogues. Systematic studies of these synthetic or natural molecules could uncover relationships between chemical structures, metal/A??/metal-A?? interactions, and inhibition of A??/metal-A?? reactivity (i.e., aggregation modes of A??/metal-A??; associated ROS production), suggesting mechanisms to refine the design strategy.Interdisciplinary investigations have demonstrated that the designed molecules and natural products control the aggregation pathways of metal-A?? species transforming their size/conformation distribution. The aptitude of these molecules to impact metal-A?? aggregation pathways, either via inhibition of A?? aggregate formation, most importantly of oligomers, or disaggregation of preformed fibrils, could originate from their formation of complexes with metal-A??. Potentially, these molecules could direct metal-A?? size/conformational states into alternative nontoxic unstructured oligomers, and control the geometry at the A??-ligated metal center for limited ROS formation to lessen the overall toxicity induced by metal-A??. Complexation between small molecules and A??/metal-A?? has been observed by nuclear magnetic resonance spectroscopy (NMR) and ion mobility-mass spectrometry (IM-MS) pointing to molecular level interactions, validating the design strategy. In addition, these molecules exhibit other attractive properties, such as antioxidant capacity, prevention of ROS production, potential blood-brain barrier (BBB) permeability, and reduction of A??-/metal-A??-induced cytotoxicity, making them desirable tools for unraveling AD complexity. In this Account, we summarize the recent development of small molecules, via both rational design and the selection and modification of natural products, as tools for investigating metal-A?? complexes, to advance our understanding of their relation to AD pathology.close5

Hypercoordination in triphenyl oxinates of the group 14 elements

The triphenyl oxinates of the group 14 elements (M = Si, Ge, Sn, and Pb) contain the 8-hydroxyquinoline ligand (HOx), which can function in either a bidentate or monodentate fashion. The compounds Ph3MOx were prepared by reaction of the triphenylmetal chloride with HOx in the presence of an HCl scavenger triethylamine or, sodium acetate, and in the case of lead, with the sodium salt of 8-hydroxyquinoline. The interaction of the nitrogen with the central atom was studied through the use of the NMR chemical shifts of the central metal atom and the 15N atom of the ligand. The chemical shifts of the central metal provided evidence that the triphenylgermanium and silicon oxinates are uncoordinated while the triphenyltin and lead oxinates are five-coordinate. These conclusions are confirmed by molecular modeling, 15N chemical shifts and the metal-13C one bond coupling constants at the ipso carbon. The NMR data provides evidence that the strength of the interaction of the nitrogen with the metal increases from silicon and germanium to lead. Two peaks in the 5-coordinate region of the 207Pb NMR spectra can be rationalized with the postulate that strong interaction with lead produces two geometrical isomers. Two peaks were also present in the 5-coordinate region of the 119Sn NMR spectra at low temperatures indicating a rapid exchange between the two geometrical isomers at room temperature. © 2009 Elsevier B.V. All rights reserved

Use of \u3csup\u3e73\u3c/sup\u3eGe NMR spectroscopy for the study of electronic interactions

The lack of understanding of the structural and electronic factors that affect the often difficult to observe germanium resonance has been a major deterrent to studies of bonding interactions at germanium. We utilized the symmetrical system GeR4 to determine what structural factors inherent in the R group affect the shape and position of the 73Ge resonance. The 73Ge resonances of symmetrical tetrakis germanium compounds of the type GeR4 (R = alkyl, aryl), GeX4 (X = F, Cl, Br, I), Ge(OR)4 (R = alkyl, methoxyalkyl, dimethylaminoalkyl), Ge(NR 2)4 (R = alkyl), and Ge(SR)4 (R = alkyl, dimethylaminoalkyl) were examined for evidence of intramolecular coordination. Although many of these compounds have sharp resonances due to idealized tetrahedral symmetry with relatively long relaxation times, others have broad or no observable resonances due to fast quadrupolar relaxation. We hypothesize that the perturbation of symmetry by even weak Lewis interactions or conformational changes causes broadening of the resonance before the interaction can become sufficiently strong to cause the significant low-frequency shift generally associated with hypercoordination in most nuclei. Intermolecular coordination to GeCl4 is believed to be responsible for the low-frequency shifts in 73Ge resonances and the associated changes in peak widths in mixtures with bases such as tributylphosphine oxide (TBPO) and triethylphosphine oxide (TEPO). Adduct formation with these bases is confirmed by broad 31P resonances that are resolved into five peaks at -40°C. The exchange-broadened resonances due to the 1:1 and 1:2 TEPO adducts are also observed at -40°C in the 73Ge spectrum. Thus, relatively strong bonding to the germanium in GeCl4 results in both low-frequency shifts and broadening of the resonance. The broad 73Ge resonances that occur in some compounds may be in part due to exchange as well as quadrupolar relaxation. © 2008 American Chemical Society

Dual-function triazole-pyridine derivatives as inhibitors of metal-induced amyloid-beta aggregation

Dysregulated metal ions are hypothesized to play a role in the aggregation of the amyloid-?? (A??) peptide, leading to Alzheimer's disease (AD) pathology. In addition to direct effects on A?? aggregation, both Cu and Fe can catalyze the generation of reactive oxygen species (ROS), possibly contributing to significant neuronal toxicity. Therefore, disruption of metal-A?? interactions has become a viable strategy for AD therapeutic development. Herein, we report a new series of dual-function triazole-pyridine ligands [4-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)morpholine (L1), 3-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)propan-1-ol (L2), 2-(4-(pyridin-2-yl)- 1H-1,2,3-triazol-1-yl)acetic acid (L3), and 5-(4-(pyridin-2-yl)-1H-1,2,3- triazol-1-yl)pentan-1-amine (L4)] that interact with the A?? peptide and modulate its aggregation in vitro. Metal chelation and A?? interaction properties of these molecules were studied by UV-vis, NMR spectroscopy and X-ray crystallography. In addition, turbidity and transmission electron microscopy (TEM) were employed to determine the anti-aggregation properties of L1-L4. All compounds demonstrated an ability to limit metal-induced A?? aggregation. Overall, our studies suggest the utility of the triazole-pyridine framework in the development of chemical reagents toward inhibitors for metal-triggered A?? aggregation.close211

Use of73Ge NMR Spectroscopy and X-ray Crystallography for the Study of electronic interactions in substituted tetrakis(phenyl)-, -(phenoxy)-, and -(thiophenoxy)germanes

NMR chemical shifts of 1H, 13C, and 73Ge, molecular modeling, and single-crystal X-ray diffraction results are reported for a series of substituted tris- and tetrakis(phenyl)germanes of the type (XC6H4)3GeY and (XC6H 4)4Ge, where X = o-, m-, and p-OCH3, o-, m-, and p-OC2H5, m- and p-CF3, H, p-C(CH 3)3, p-Cl; and Y = Cl and H. Chemical shifts and X-ray data are also reported for o-CH3 and o-OCH3 tetrakis(phenoxy)- ((XC6H4O)4Ge) and thiophenoxygermanes ((XC6H4S)4Ge). For tetrakis derivatives, 73Ge resonances are observed for all but the o-methoxyphenoxy compound, for which the inability to detect a resonance is attributed to rapid quadrupolar relaxation caused by intramolecular interactions of the methoxy oxygen with the central atom. The observation of a relatively broad, slightly upfield 73Ge resonance in the analogous phenyl and thiophenoxy derivatives suggests, as do the results of molecular modeling, that in these compounds there is some hypercoordination. The solid-state structures show bond angles at the aromatic carbon bearing the alkoxy group that suggest an interaction of the alkoxy oxygen with germanium. Oxygen-germanium bond distances are about 17% shorter than the sum of the van der Waals radii. © 2010 American Chemical Society

Abnormal metal levels in the primary visual pathway of the DBA/2J mouse model of glaucoma

The purpose of this study was to determine metal ion levels in central visual system structures of the DBA/2J mouse model of glaucoma. We used inductively coupled plasma mass spectrometry (ICPMS) to measure levels of iron (Fe), copper (Cu), zinc (Zn), magnesium (Mg), manganese (Mn), and calcium (Ca) in the retina and retinal projection of 5-month (pre-glaucomatous) and 10-month (glaucomatous) old DBA/2J mice and age-matched C57BL/6J controls. We used microbeam X-ray fluorescence (??-XRF) spectrometry to determine the spatial distribution of Fe, Zn, and Cu in the superior colliculus (SC), which is the major retinal target in rodents and one of the earliest sites of pathology in the DBA/2J mouse. Our ICP-MS experiments showed that glaucomatous DBA/2J had lower retinal Fe concentrations than pre-glaucomatous DBA/2J and age-matched C57BL/6J mice. Pre-glaucomatous DBA/2J retina had greater Mg, Ca, and Zn concentrations than glaucomatous DBA/2J and greater Mg and Ca than age-matched controls. Retinal Mn levels were significantly deficient in glaucomatous DBA/2J mice compared to agedmatched C57BL/6J and pre-glaucomatous DBA/2J mice. Regardless of age, the SC of C57BL/6J mice contained greater Fe, Mg, Mn, and Zn concentrations than the SC of DBA/2J mice. Greater Fe concentrations were measured by ??-XRF in both the superficial and deep SC of C57BL/6J mice than in DBA/2J mice. For the first time, we show direct measurement of metal concentrations in central visual system structures affected in glaucoma and present evidence for strain-related differences in metal content that may be specific to glaucomatous pathology.close0

Development of Bifunctional Stilbene Derivatives for Targeting and Modulating Metal-Amyloid-β Species

Amyloid-β (Aβ) peptides and their metal-associated aggregated states have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the etiology of AD remains uncertain, understanding the role of metal-Aβ species could provide insights into the onset and development of the disease. To unravel this, bifunctional small molecules that can specifically target and modulate metal-Aβ species have been developed, which could serve as suitable chemical tools for investigating metal-Aβ-associated events in AD. Through a rational structure-based design principle involving the incorporation of a metal binding site into the structure of an Aβ interacting molecule, we devised stilbene derivatives (<b>L1-a</b> and <b>L1-b</b>) and demonstrated their reactivity toward metal-Aβ species. In particular, the dual functions of compounds with different structural features (e.g., with or without a dimethylamino group) were explored by UV–vis, X-ray crystallography, high-resolution 2D NMR, and docking studies. Enhanced bifunctionality of compounds provided greater effects on metal-induced Aβ aggregation and neurotoxicity in vitro and in living cells. Mechanistic investigations of the reaction of <b>L1-a</b> and <b>L1-b</b> with Zn²⁺-Aβ species by UV–vis and 2D NMR suggest that metal chelation with ligand and/or metal–ligand interaction with the Aβ peptide may be driving factors for the observed modulation of metal-Aβ aggregation pathways. Overall, the studies presented herein demonstrate the importance of a structure-interaction-reactivity relationship for designing small molecules to target metal-Aβ species allowing for the modulation of metal-induced Aβ reactivity and neurotoxicity