Unusual Cyclodextrin Derivatives as a New Avenue to Modulate Self‐ and Metal‐Induced Aβ Aggregation

Mounting evidence suggests an important role of cyclodextrins in providing protection in neurodegenerative disorders. Metal dyshomeostasis is reported to be a pathogenic factor in neurodegeneration because it could be responsible for damage involving oxidative stress and protein aggregation. As such, metal ions represent an effective target. To improve the metal‐binding ability of cyclodextrin, we synthesized three new 8‐hydroxyquinoline‐cyclodextrin conjugates with difunctionalized cyclodextrins. In particular, the 3‐difunctionalized regioisomer represents the first example of cyclodextrin with two pendants at the secondary rim, resulting in a promising compound. The derivatives have significant antioxidant capacity and the powerful activity in inhibiting self‐induced amyloid‐β aggregation seems to be led by synergistic effects of both cyclodextrin and hydroxyquinoline. Moreover, the derivatives are also able to complex metal ions and to inhibit metal‐induced protein aggregation. Therefore, these compounds could have potential as therapeutic agents in diseases related to protein aggregation and metal dyshomeostasis.     

Zinc Complexes of Cyclodextrin‐bearing 8‐Hydroxyquinoline Ligands: A Comparative Study

The mounting evidence supporting the role of metal ions in several diseases has turned metal‐ion chelation therapy into a promising treatment strategy. The design of efficient metal‐binding ligands requires in‐depth knowledge of molecular structure and stability constants of the complexes formed. This paper presents an extensive overview on the stability of zinc(II) and copper(II) complexes of a series of cyclodextrin‐8‐hydroxyquinoline conjugates. In order to explain the differences observed in the stability constants between the metal complexes of the 6‐functionalized and 3‐functionalized cyclodextrin isomers, conformational analysis and DFT simulations were also performed. Molecular simulations allowed us to clarify the binding mode and to explain the differences in the stability constants of the metal complexes of these derivatives.     

Multifunctional 8‐Hydroxyquinoline‐Appended Cyclodextrins as New Inhibitors of Metal‐Induced Protein Aggregation

Mounting evidence suggests a pivotal role of metal imbalances in protein misfolding and amyloid diseases. As such, metal ions represent a promising therapeutic target. In this context, the synthesis of chelators that also contain complementary functionalities to combat the multifactorial nature of neurodegenerative diseases is a highly topical issue. We report two new 8‐hydroxyquinoline‐appended cyclodextrins and highlight their multifunctional properties, including their Cu^II and Zn^II binding abilities, and capacity to act as antioxidants and metal‐induced antiaggregants. In particular, the latter property has been applied in the development of an effective assay that exploits the formation of amyloid fibrils when β‐lactoglobulin A is heated in the presence of metal ions.     

New Cyclodextrin‐Bearing 8‐Hydroxyquinoline Ligands as Multifunctional Molecules

Recent investigations have rekindled interest in 8‐hydroxyquinolines as therapeutic agents for cancer, Alzheimer’s disease, and other neurodegenerative disorders. Three new β‐cyclodextrin conjugates of 8‐hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.     

New diazadi(and tri)thia‐21‐crown‐7 ethers containing 8‐hydroxyquinoline side arms

A series of macrocyclic diazadi(and tri)thiacrown ethers containing two 5‐substituent‐8‐hydroxyquinoline side arms have been synthesized from the corresponding macrocyclic diazadi(and tri)thiacrown ethers. The crown ethers were obtained by reduction of the proper macrocyclic di(and tri)thiadiamides by borane‐tetrahydrofuran or by sodium borohydride‐boron trifluoride ethyl etherate‐tetrahydrofuran. The yields for the reduction of diamides by sodium borohydride‐boron trifluoride ethyl etherate‐tetrahydrofuran were higher than those by borane‐tetrahydrofuran. The following four methods were used to prepare macrocycles bearing two 8‐hydroxyquinoline side arms: (1) Mannich reaction with 8‐hydroxyquinoline; (2) Reductive animation with 8‐hydroxyquinoline‐2‐carboxaldehyde using sodium triacetoxyborohydride as the reducing agent; (3) Cyclization of N,N'‐bis(8‐hydroxyquinolin‐2‐ylmethyl)‐1,2‐bis(2‐aminoethoxy)ethane (38) with bis(α‐chloroamide) 5 ; and ( 4 ) A step‐by‐step process wherein macrocyclic trithiadiamide 11 was reduced by lithium aluminum hydride‐tetrahydrofuran to the cyclic monoamide 36 , which smoothly reacted with 5‐chloro‐8‐hydroxyquinoline to produce monosubstituted‐macrocyclic monoamide 39 .     

Transfer of Copper from an Amyloid to a Natural Copper‐Carrier Peptide with a Specific Mediating Ligand

The oxidative stress that arises from the catalytic reduction of dioxygen by Cu^II/I‐loaded amyloids is the major pathway for neuron death that occurs in Alzheimer’s disease. In this work, we show that bis‐8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu^II from Cu–Aβ_1–16 and then completely release Cu^I in the presence of glutathione to provide a Cu^I–glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper–protein complexes. These data demonstrate that bis‐8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu–amyloid complexes to regular copper–protein complexes. These copper‐specific ligands assist GSH to recycle Cu^I in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer’s disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8‐hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu–β‐amyloid complexes.     

Influence of substituent position and cavity size of the regioisomers of monocarboxymethyl‐α‐, β‐, and γ‐cyclodextrins on the apparent stability constants of their complexes with both enantiomers of Tröger's base

Enantiomers of Tröger's base were separated by capillary electrophoresis using 2^I‐O‐, 3^I‐O‐, and 6^I‐O‐carboxymethyl‐α‐, β‐, and γ‐cyclodextrin and native α‐, β‐, and γ‐cyclodextrin as chiral additives at 0–12 mmol/L for β‐cyclodextrin and its derivatives and 0–50 mmol/L for α‐ and γ‐cyclodextrins and their derivatives in a background electrolyte composed of sodium phosphate buffer at 20 mmol/L concentration and pH 2.5. Apparent stability constants of all cyclodextrin–Tröger's base complexes were calculated based on capillary electrophoresis data. The obtained results showed that the position of the carboxymethyl group as well as the cavity size of the individual cyclodextrin significantly influences the apparent stability constants of cyclodextrin–Tröger's base complexes.     

Histidine‐Rich Oligopeptides To Lessen Copper‐Mediated Amyloid‐β Toxicity

Brain copper imbalance plays an important role in amyloid‐β aggregation, tau hyperphosphorylation, and neurotoxicity observed in Alzheimer's disease (AD). Therefore, the administration of biocompatible metal‐binding agents may offer a potential therapeutic solution to target mislocalized copper ions and restore metallostasis. Histidine‐containing peptides and proteins are excellent metal binders and are found in many natural systems. The design of short peptides showing optimal binding properties represents a promising approach to capture and redistribute mislocalized metal ions, mainly due to their biocompatibility, ease of synthesis, and the possibility of fine‐tuning their metal‐binding affinities in order to suppress unwanted competitive binding with copper‐containing proteins. In the present study, three peptides, namely HWH , HK^CH , and HAH , have been designed with the objective of reducing copper toxicity in AD. These tripeptides form highly stable albumin‐like complexes, showing higher affinity for Cu^II than that of Aβ(1‐40). Furthermore, HWH , HK^CH , and HAH act as very efficient inhibitors of copper‐mediated reactive oxygen species (ROS) generation and prevent the copper‐induced overproduction of toxic oligomers in the initial steps of amyloid aggregation in the presence of Cu^II ions. These tripeptides, and more generally small peptides including the sequence His‐Xaa‐His at the N‐terminus, may therefore be considered as promising motifs for the future development of new and efficient anti‐Alzheimer drugs.     

8‐Hydroxy Quinoline Derivatives as Auxiliary Ligands for Red‐Emitting Cyclic‐Platinum Phosphorescent Complexes: Synthesis and Properties

Heavy metal complexes exhibit high phosphorescent efficiency and have been used extensively for electrophosphorescent emitters in the past 16 years. In 2006, we initially reported the use of the popular ligand, 8‐hydroxyquinoline (Q) to coordinate with the heavy metal ions and obtained the red‐infrared phosphorescent emission. In this paper, 8‐hydroxyquinoline has been modified at the 5‐position by electron‐donating and attracting groups and platinum complexes based on 2‐phenylpyridine and 8‐hydroxyquinoline derivatives were synthesized. The electron‐withdrawing group CF ₃ and NO ₂ lowers the HOMO level of the Q ligand and results in a N^O centered enhanced red‐infrared phosphorescence emission. The complex with CF ₃ modification exhibits the highest phosphorescence quantum yield in solid state with a life time of 1.17 μs.     

Heterocycles Derived from 5‐(2‐Aminothiazol‐4‐yl)‐8‐hydroxyquinoline: Synthesis and Antimicrobial Activity

5‐(2‐Aminothiazol‐4‐yl)‐8‐hydroxyquinoline 2 has been synthesized by treating thiourea with 5‐chloroacetyl‐8‐hydroxyquinoline 1 . The amine 2 was treated with aromatic aldehydes to furnish schiff bases 6a‐c which on treatment with phenyl isothiocyanate gave the corresponding thiazolo‐s‐triazines 7a‐c . Reaction of 2 with phenyl isothiocyanate gave the corresponding aminocarbothiamide derivative 8 which on reaction with malonic acid in acetyl chloride afforded thiobarbituric acid derivative 9 . Coupling of 9 with diazonium salt gave the phenyl hydrazono derivative 10 . However, reaction of 2 with carbon disulphide and methyl iodide afforded dithiocarbamidate 12 which on treatment with ethylenediamine, o‐aminophenol and/or phenylenediamine gave the aminoazolo derivatives 13–15 , respectively. Other substituted fused thiazolopyrimidines 16–20 have been also prepared by the reaction of 2 with some selected dicarbonyl reagents. The characterisation of synthesized compounds has been done on the basis of elemental analysis, IR, ¹H‐NMR and mass spectral data. All the newly synthesized compounds have been screened for their antimicrobial activities.     

Homo‐ and Heterodinuclear Helicates of Lanthanide(III), Zinc(II) and Aluminium(III) Based on 8‐Hydroxyquinoline Ligands

Homonuclear helicates with rare‐earth‐metal(III) ions or heteronuclear derivatives with rare‐earth‐metal and aluminium or zinc centres are obtained in alkali‐metal‐templated self‐assembly processes from isobutenylidene‐bridged homoditopic bis(2‐carbamido‐8‐hydroxyquinoline)‐derived ligands 1 ? H₂ and 2 ? H₂ or heteroditopic (8‐hydroxyquinoline)(2‐carbamido‐8‐hydroxyquinoline)‐derived ligands 3 ? H₂ and 4 ? H₂. Diamagnetic coordination compounds possess a high stability in organic solvents such as CDCl₃, [D₄]MeOH or [D₆]DMSO and can be well characterised by ¹H NMR spectroscopy by using methylene protons and the protons of the vinylic units of the ligand as stereochemical or symmetry probes, respectively. Some of the homonuclear complexes could be crystallised and were characterised by using X‐ray diffraction studies. The complexes adopt a triple‐stranded helical structure with a central templating cation encapsulated in their interior. An unusual orientation of the double bond of one spacer towards this cation is observed. The homo‐ and heterodinuclear helicates with ytterbium(III), neodymium(III) or erbium(III) of ligands 2 and 4 were of special interest owing to their near‐infrared (NIR) emitting properties, which were investigated depending on the lanthanide and on the encapsulated alkali‐metal cation.     

The characteristic of photoluminescence of tris‐(7‐substituted‐8‐hydroxyquinoline) aluminum complexes and polymeric complexes

The 7‐allyl‐ and 7‐(2‐methylvinyl)‐functionalized derivatives of 8‐hydroquinoline are synthesized by Claisen rearrangement and double bond rearrangement respectively. Then 7‐allyl‐8‐hydroquinoline (C) and 7‐(2‐methylvinyl)‐8‐hydroquinoline (D) are reacted with aluminum chloride to afford the corresponding tris‐(7‐allyl‐8‐hydroxyquinoline) aluminum complex (F) and tris‐(7‐(2‐methylvinyl)‐8‐hydroxyquinoline) aluminum complex (G). The photoluminescence of complex (F) or (G), compared with that of tris‐(8‐hydroxyquinoline) aluminum complex (E), all showed a red shift in emission wavelengths in different solvents, such as chloroform, hexane and ethanol. For two substituents containing an external double bond, the 2‐methylvinyl group gives a larger red shift in the emission wavelength than the allyl group. The X‐ray crystal structure indicates that 7‐(2‐methylvinyl)‐8‐hydroxyquinoline (D) is a trans‐isomer. The styrene and 7‐allyl‐8‐hydroxyquinoline copolymer, and the styrene and 7‐(2‐methylvinyl)‐8‐hydroxyquinoline copolymer are also reported. Further reactions of the copolymer are then performed by adding aluminum(III) chloride and ligands 8‐hydroxyquinoline. The spectroscopic characteristics of these aluminum(III) polymeric complexes are discussed. Copyright © 2003 John Wiley & Sons, Ltd.     

Incubation with Cu(II) and Zn(II) salts enhances MALDI‐TOF mass spectra of amyloid‐beta and α‐synuclein toward in vivo analysis

Insoluble senile plaque aggregates are indicative of Alzheimer's disease pathology. A similar phenomenon occurs in Parkinson's disease with the build‐up of Lewy bodies. The analysis of senile plaques, and other brain samples, from Alzheimer's disease and Parkinson's disease patients by matrix‐assisted laser desorption/ionization mass spectrometry has advantages but also presents obstacles because of the nature of the processes utilized in isolation procedures and storage. Salts, buffers, and detergents necessary in the isolation of biological species may cause adducts and ion suppression that convolute the spectra obtained. We previously determined that amyloid‐beta from isolated senile plaque deposits fragment similarly to the synthetic 40 and 42 amino acid peptide when analyzed by matrix‐assisted laser desorption/ionization mass spectrometry. In addition, α‐synuclein also fragments predictably by in‐source decay. This provides information that may be applied to the identification and localization of amyloid‐beta and α‐synuclein in senile plaques and intact tissue sections. Ion suppression must still be accounted for when analyzing biological samples, which makes identifying fragments at lower abundance difficult. The addition of certain transition‐metal salts (Cu(II), Zn(II)) to the sample prior to analysis serves to “clean” the spectra and allow the peptide fragments produced to be observed with a much higher signal to noise and occasionally, improved resolution. We present a systematic study of incubation with different metal salts and their impact on the quality of the spectra, as well as the role of the binding of the metals to the model biological compounds, obtained for synthetic amyloid‐beta, synthetic α‐synuclein, and isolated senile plaques. The optimized sample preparation methods presented will provide for simpler and more thorough identification of these biologically relevant species in human‐derived samples.     

Novel D − π − A dye sensitizers of polymeric metal complexes based on 8‐hydroxyquinoline and phenylethyl or fluorene units: synthesis,characterization and photovoltaic applications for dye‐sensitized solar cells

Four novel donor ? π‐bridge ? acceptor (D ? π ? A) polymeric metal complexes (P1–P4) based on 8‐hydroxyquinoline metal complexes were synthesized and tested for their performance in dye‐sensitized solar cells (DSSCs). The polymeric metal complexes dyes use alkoxy benzene or alkyl fluorene as the electron donor and C=C as π linker; the 8‐hydroxyquinoline derivative complex part was used as the electron acceptor and diaminomaleonitrile was used as ancillary ligand. The two strongly electron‐withdrawing cyano groups in the polymer structure can provide an efficient charge transport in the intramolecular between donor and acceptor parts. The thermal, photophysical, electrochemical and photovoltaic properties of these copolymers were investigated by TGA, differential scanning calorimetry, cyclic voltammetry and cureent density‐voltage curves, and the results showed that dye containing complex Zn(II) and alkoxy benzene unit benefited the generation of photocurrent and open‐circuit voltages, and a maximum power conversion efficiency of 1.91% (P2) was obtained, with an open‐circuit voltage of 0.71 V, a short‐circuit current density of 4.23 mA cm^?2, and a fill factor of 38.6% under AM1.5G irradiation. The study results also show that the four polymers exhibit good thermal stability, indicating that these polymeric metal complexes are suitable for the fabrication processes of optoelectronic devices. Copyright © 2013 John Wiley & Sons, Ltd.     

Optical Structural Analysis of Individual α‐Synuclein Oligomers

Small aggregates of misfolded proteins play a key role in neurodegenerative disorders. Such species have proved difficult to study due to the lack of suitable methods capable of resolving these heterogeneous aggregates, which are smaller than the optical diffraction limit. We demonstrate here an all‐optical fluorescence microscopy method to characterise the structure of individual protein aggregates based on the fluorescence anisotropy of dyes such as thioflavin‐T, and show that this technology is capable of studying oligomers in human biofluids such as cerebrospinal fluid. We first investigated in vitro the structural changes in individual oligomers formed during the aggregation of recombinant α‐synuclein. By studying the diffraction‐limited aggregates we directly evaluated their structural conversion and correlated this with the potential of aggregates to disrupt lipid bilayers. We finally characterised the structural features of aggregates present in cerebrospinal fluid of Parkinson's disease patients and age‐matched healthy controls.     

Ethylene polymerization by novel Ziegler–Natta‐type catalysts obtained in situ by the oxidative addition of 8‐hydroxyquinoline‐based ligands to bis(1,5‐cyclooctadiene)nickel(0) and methylaluminoxane

Novel catalytic systems, prepared in situ by the oxidative addition of 8‐hydroxyquinoline ligands to bis(1,5‐cyclooctadiene)nickel(0) and activated by methylaluminoxane, were studied in ethylene polymerization. When 8‐hydroxyquinoline was employed, only oligomeric products were obtained. On the contrary, 5,7‐dinitro‐8‐hydroxyquinoline gave linear polyethylene (PE), but with a modest activity. For the catalyst based on 5‐nitro‐8‐hydroxyquinoline, the productivity was largely dependent on the content of free trimethylaluminum (TMA) present in the commercial aluminoxane. The progressive optimization of the TMA/oligomeric methylaluminoxane ratio increased the productivity, which reached 700 kg of PE/(mol of Ni × h), by an order of magnitude. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 200–206, 2006     

Sequestration of a β‐Hairpin for Control of α‐Synuclein Aggregation

The misfolding and aggregation of the protein α‐synuclein (α‐syn), which results in the formation of amyloid fibrils, is involved in the pathogenesis of Parkinson’s disease and other synucleinopathies. The emergence of amyloid toxicity is associated with the formation of partially folded aggregation intermediates. Here, we engineered a class of binding proteins termed β‐wrapins (β‐wrap proteins) with affinity for α‐synuclein (α‐syn). The NMR structure of an α‐syn:β‐wrapin complex reveals a β‐hairpin of α‐syn comprising the sequence region α‐syn(37–54). The β‐wrapin inhibits α‐syn aggregation and toxicity at substoichiometric concentrations, demonstrating that it interferes with the nucleation of aggregation.     

Contact between the β1 and β2 Segments of α‐Synuclein that Inhibits Amyloid Formation

Conversion of the intrinsically disordered protein α‐synuclein (α‐syn) into amyloid aggregates is a key process in Parkinson’s disease. The sequence region 35–59 contains β‐strand segments β1 and β2 of α‐syn amyloid fibril models and most disease‐related mutations. β1 and β2 frequently engage in transient interactions in monomeric α‐syn. The consequences of β1–β2 contacts are evaluated by disulfide engineering, biophysical techniques, and cell viability assays. The double‐cysteine mutant α‐synCC, with a disulfide linking β1 and β2, is aggregation‐incompetent and inhibits aggregation and toxicity of wild‐type α‐syn. We show that α‐syn delays the aggregation of amyloid‐β peptide and islet amyloid polypeptide involved in Alzheimer’s disease and type 2 diabetes, an effect enhanced in the α‐synCC mutant. Tertiary interactions in the β1–β2 region of α‐syn interfere with the nucleation of amyloid formation, suggesting promotion of such interactions as a potential therapeutic approach.     

Synthesis and Characterization of β—Cyclodextrin Bonded Metal Porphyrins

Reactions of 5-(p-aminophenyl)-10,15,20-triphenyl porphyrin (1) with Ru3(CO)12 or M(OCOCH3)2 (M=Ni,Mn) afforded metalloporphyrins(4-6),respectively.6-Deoxy-6-io-do-β-cyclodextrin(2) and mono(6-O-trifluoromethanesulfonyl) permethylated β-cyclodextrin(3) reacted with complexes 4-6 to give β-cyclodextrin bonded metal porphyrins (7-9) and permethylated β-cyclodextrin bonded me-tal porphyrins (10-12) respectively.These new complexes were identified by MS,IR,UV-visible and ^1H NMR spectra,and elemental analysis.     

8‐Hydroxyquinoline Functionalized PEG‐1000 Bridged Dicationic Ionic Liquid as a Novel Ligand for Copper‐catalyzed N‐Arylation of Imidazoles

A novel 8‐hydroxyquinoline functionalized PEG‐1000 bridged dicationic ionic liquid ([HQ‐PEG₁₀₀₀‐DIL][BF₄]) was synthesized and characterized. It was applied as an efficiently recyclable ligand for copper‐catalyzed N‐arylation of nitrogen‐containing heterocycles with aryl halides. The catalytic system could be easily recovered and reused for at least five runs without obvious loss of catalytic activity.