The art of building multifunctional metal-binding agents from basic molecular scaffolds for the potential application in neurodegenerative diseases

Rodríguez‐Rodríguez, Cristina; Telpoukhovskaia, Maria; Orvig, Chris

doi:10.1016/j.ccr.2012.03.008

Cited by 142 publications

(219 citation statements)

References 302 publications

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“…The involvement of metal-Aβ species in AD pathogenesis, however, has not been clearly elucidated. To advance our understanding of the potential neurotoxicity of metal-Aβ species, efforts to develop chemical tools capable of interacting directly with metal-Aβ species and modulating their reactivity in vitro and in biological systems are under way (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). In particular, novel bifunctional compounds that contain elements for metal chelation and Aβ interaction have recently been prepared or identified via rational structure-based design strategies or systematic selection of natural products.…”

mentioning

confidence: 99%

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Hyung¹,

DeToma²,

Brender

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

219

268

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Despite the significance of Alzheimer's disease, the link between metal-associated amyloid-β (metal-Aβ) and disease etiology remains unclear. To elucidate this relationship, chemical tools capable of specifically targeting and modulating metal-Aβ species are necessary, along with a fundamental understanding of their mechanism at the molecular level. Herein, we investigated and compared the interactions and reactivities of the green tea extract, (−)-epigallocatechin-3-gallate [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate; EGCG], with metal [Cu(II) and Zn(II)]-Aβ and metal-free Aβ species. We found that EGCG interacted with metal-Aβ species and formed small, unstructured Aβ aggregates more noticeably than in metal-free conditions in vitro. In addition, upon incubation with EGCG, the toxicity presented by metalfree Aβ and metal-Aβ was mitigated in living cells. To understand this reactivity at the molecular level, structural insights were obtained by ion mobility-mass spectrometry (IM-MS), 2D NMR spectroscopy, and computational methods. These studies indicated that (i) EGCG was bound to Aβ monomers and dimers, generating more compact peptide conformations than those from EGCGuntreated Aβ species; and (ii) ternary EGCG-metal-Aβ complexes were produced. Thus, we demonstrate the distinct antiamyloidogenic reactivity of EGCG toward metal-Aβ species with a structurebased mechanism.amyloid-β peptide | metal ions | natural products | amyloidogenesis T he brain of individuals with Alzheimer's disease (AD) has protein aggregates composed of misfolded amyloid-β (Aβ) peptides (1-4). The Aβ peptides are produced endogenously through enzymatic cleavage of amyloid precursor protein. Aβ monomers can misfold and oligomerize into various intermediates before the formation and elongation of fibrils that exhibit a characteristic cross-β-sheet structure (1-4). The accumulation of aggregated Aβ species has been a key feature of the amyloid cascade hypothesis, which cites that these aggregates are possible causative agents in AD. In addition, transition metals, such as Cu and Zn, whose misregulation leads to aberrant neuronal function, have a suggested link to AD pathology (1,(3)(4)(5)(6)(7)(8). In vitro and in vivo studies have provided evidence for the direct interactions of metal ions with Aβ and their presence within Aβ plaques, indicating the formation of metal-associated Aβ (metal-Aβ) species. These metal-Aβ species have been implicated in processes that could lead to neurotoxicity (e.g., metal-induced Aβ aggregation and metal-Aβ-mediated reactive oxygen species generation) (1, 3-8). The involvement of metal-Aβ species in AD pathogenesis, however, has not been clearly elucidated. To advance our understanding of the potential neurotoxicity of metal-Aβ species, efforts to develop chemical tools capable of interacting directly with metal-Aβ species and modulating their reactivity in vitro and in biological systems are under way (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)...

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mentioning

confidence: 99%

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Hyung¹,

DeToma²,

Brender

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

219

268

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“…To overcome TAC drawbacks, this compound has been used as an inspiration for the development of multi-target analogues [4] in conjugation with natural moieties such as melatonin [5], hydroxyquinoline [6] or thioflavine [7], in order to combine the AChE inhibition with antioxidant properties, metal-binding capacity and/or inhibition of Aβ aggregation. Continuing our research on the development of multifunctional heterocyclic compounds with potential application in AD [7][8][9], and taking also in account the recent interest on the neuro-protective role of some natural products, hybrid compounds containing TAC and also S-allyl-cysteine (SAC, garlic constituent) or S-propargyl-cysteine (SPRC, attenuator of spatial learning and memory impairment [10]) moieties were designed and developed [11].…”

Section: Introductionmentioning

confidence: 99%

Copper(II) complexation of tacrine hybrids with potential anti-neurodegenerative roles

Quintanova

Keri

Chaves

et al. 2015

Journal of Inorganic Biochemistry

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“…AD is recognized as a multi-faceted disorder in which the patient brain shows protein misfolding and aggregation [2]. It has been established that there are several factors responsible for the neurodegeneration among which the role of metal ions have caught especial attention [1b,2b,3]. Studying the role of metal ions is also a challenging research topic [4].…”

Section: Introductionmentioning

confidence: 99%

“…Oxidative stress and free radical formation and role of metal ions like Cu and Fe in these processes is strongly indicated in recent research [4,5]. Therefore, inorganic chemistry of biological systems with special emphasis on metal ion dyshomeostasis in neurodegenerative diseases has been stimulated greatly in recent years [3a,3c,6]. …”

Section: Introductionmentioning

confidence: 99%

Azo-dyes based small bifunctional molecules for metal chelation and controlling amyloid formation

Rana

Cho

Roy

et al. 2018

Inorganica Chimica Acta

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Chemical tools are needed to discover new effective drugs for tackling multifaceted complex neurodegenerative diseases like Alzheimer’s disease (AD). Multifunctional nature of two compounds, 5-((4-nitro-phenyl)diazenyl)quinolin-8-ol (HL1) and 4-((4-nitrophenyl)diazenyl)benzene-1,3-diol (HL2) is reported w.r.t. their ability to bind Cu2+ ions and amyloid aggregates related to AD. HL1 and HL2 have half congo-red type azo-stilbene structural framework incorporated with metal chelating groups, designed to chelate metal ions from metal-amyloid species. Metal binding studies of HL1 and HL2 are established by the methods of Job’s Plot, UV-vis spectra with metal ions and stability constant determination. In addition, their metal complexes are isolated, purity checked by elemental analysis, spectroscopically characterized and their structural analyses were obtained from DFT based calculations including binding energy determination. Chicken egg white Lysozyme (CEWL) was used as a model peptide for fibrillation studies. HL1 is found as an excellent colorimetric sensor for amyloid fibrils. Inhibitory effect of HL1 and HL2 and their isolated metal complexes L1-Cu and L2-Cu on CEWL fibrillation was studied using ThT and ANS fluorescence assay along with TEM imaging. In addition, the cell toxicity studies on these compounds suggest that although azo dyes may be non-toxic but having a nitro-substitution lead to significant cell toxicity. Overall, these results suggest that this new class of multifunctional small molecules can interact with amyloids as well as metal ions and could be potential anti-aggregation metal chelating agents.

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The art of building multifunctional metal-binding agents from basic molecular scaffolds for the potential application in neurodegenerative diseases

Cited by 142 publications

References 302 publications

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Copper(II) complexation of tacrine hybrids with potential anti-neurodegenerative roles

Azo-dyes based small bifunctional molecules for metal chelation and controlling amyloid formation

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