Design of functionalized β-ketoenole derivatives as efficient fluorescent dyes for detection of amyloid fibrils

Kovalska, Vladyslava; Chernii, Svitlana; Losytskyy, Mykhaylo Yu.; Tretyakova, Iryna; Dovbii, Yan; Gorski, Aleksander; Chernii, Viktor; Czerwieniec, Rafał; Yarmoluk, S. M.

doi:10.1039/c8nj01020j

Cited by 17 publications

(15 citation statements)

References 36 publications

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“…Besides ThT and CR, other compounds have been also used for the detection of amyloid fibrils [39][40][41][42]. The search for novel, more sensitive and blood-brain barrier crossing dyes for detecting the initial stages and more toxic oligomeric species involved in fibril formation in vitro, ex vivo and in vivo is still under way [43][44][45]. Nevertheless, several related structures or derivatives of both CR [46][47][48][49] and ThT [50][51][52][53] have been shown to be quite helpful for both in vitro and ex vivo identification of amyloid fibrils ( Figure 2).…”

Section: The Tinctorial Properties Of Amyloid Fibrilsmentioning

confidence: 99%

Structure and Aggregation Mechanisms in Amyloids

2020

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The aggregation of a polypeptide chain into amyloid fibrils and their accumulation and deposition into insoluble plaques and intracellular inclusions is the hallmark of several misfolding diseases known as amyloidoses. Alzheimer′s, Parkinson′s and Huntington’s diseases are some of the approximately 50 amyloid diseases described to date. The identification and characterization of the molecular species critical for amyloid formation and disease development have been the focus of intense scrutiny. Methods such as X-ray and electron diffraction, solid-state nuclear magnetic resonance spectroscopy (ssNMR) and cryo-electron microscopy (cryo-EM) have been extensively used and they have contributed to shed a new light onto the structure of amyloid, revealing a multiplicity of polymorphic structures that generally fit the cross-β amyloid motif. The development of rational therapeutic approaches against these debilitating and increasingly frequent misfolding diseases requires a thorough understanding of the molecular mechanisms underlying the amyloid cascade. Here, we review the current knowledge on amyloid fibril formation for several proteins and peptides from a kinetic and thermodynamic point of view, the structure of the molecular species involved in the amyloidogenic process, and the origin of their cytotoxicity.

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Section: The Tinctorial Properties Of Amyloid Fibrilsmentioning

confidence: 99%

Structure and Aggregation Mechanisms in Amyloids

2020

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“…Recently, we have discovered β-ketoenoles as a new class of dyes possessing fluorescence sensitivity to amyloid fibrils [ 15 , 16 ]. These compounds are able to specifically bind to the amyloid fibrils with the increase of fluorescent quantum yield and lifetime, while demonstrating a relatively weak response in the presence of native protein.…”

Section: Introductionmentioning

confidence: 99%

Modification of insulin amyloid aggregation by Zr phthalocyanines functionalized with dehydroacetic acid derivatives

et al. 2021

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Amyloid fibrils are widely studied both as target in conformational disorders and as basis for the development of protein-based functional materials. The three Zr phthalocyanines bearing dehydroacetic acid residue (PcZr(L1)2) and its condensed derivatives (PcZr(L2)2 and PcZr(L3)2) as out-of-plane ligands were synthesized and their influence on insulin fibril formation was studied by amyloid-sensitive fluorescent dye based assay, scanning electron microscopy, fluorescent and absorption spectroscopies. The presence of Zr phthalocyanines was shown to modify the fibril formation. The morphology of fibrils formed in the presence of the Zr phthalocyanines differs from that of free insulin and depends on the structure of out-of-plane ligands. It is shown that free insulin mostly forms fibril clusters with the length of about 0.3–2.1 μm. The presence of Zr phthalocyanines leads to the formation of individual 0.4–2.8 μm-long fibrils with a reduced tendency to lateral aggregation and cluster formation (PcZr(L1)2), shorter 0.2–1.5 μm-long fibrils with the tendency to lateral aggregation without clusters (PcZr(L2)2), and fibril-like 0.2–1.0 μm-long structures (PcZr(L3)2). The strongest influence on fibrils morphology made by PcZr(L3)2 could be explained by the additional stacking of phenyl moiety of the ligand with aromatic amino acids in protein. The evidences of binding of studied Zr phthalocyanines to mature fibrils were shown by absorption spectroscopy (for PcZr(L1)2 and PcZr(L2)2) and fluorescent spectroscopy (for PcZr(L3)2). These complexes could be potentially used as external tools allowing the development of functional materials on protein fibrils basis.

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“…Механізм цієї реакції вивчався у роботах [31,32]: вона відбувається через нуклеофільну атаку 6-вуглецевого атома піранового циклу халкону, що веде до його розмикання та декарбоксилювання. Ми виявили, що на першому етапі цієї реакції взаємодія халконів з амінами (рис.…”

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“…2) приводить до утворення відповідної солі (у випадку третбутиламіну реакція зупиняється на цій стадії). При нагріванні сіль дисоціює і одночасно аміногрупа ата-кує атом вуглецю метильної групи в пірановому кільці, що викликає розмикання циклу з наступним декарбоксилюванням [31,32] кути свідчать про те, що всі ці сполуки можуть мати подібні хелатуючі властивості. Відомо, що -кетоєноли (у літературі часто відомі як -дикетони, або -дикарбонільні сполуки) є кон'югованими системами, у яких вміст єнольної форми досить високий.…”

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CRYSTAL STRUCTURE AND TAUTOMERISM OF ALKYLAMINO-β-KETOENOLS IN SOLUTIONS

Chernii

2019

Ukr. Chem. Journ.

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The structure of alkylamino-β-ketoenols obtained by opening of the pyran cycle of chalcones based on dehydracetic acid was studied by X-ray diffraction, IR, 1H NMR spectroscopy and chromatography-mass spectrometry. The infrared spectra of the compounds appear to be typical of β-ketoenols. The crystalline structure (2Z,5Z,7E,9E)-6-hydroxy-2-(methylami-no)-10-phenylethoxy-2,5,7,9-tetraene-4-one was first determined. A comparative analysis of it with 2 pre-viously published structures has been carried out. All of these compounds are crystallized in the form of yellow plates in the monoclinic crystalline system (spatial group P21/n), they have a planar arrangement of the polyene chain and β-ketoenol fragment con-jugated to the aromatic ring. It has been established that the planar configuration of the β-ketoenol fragment is stabilized by hydrogen bonds between the hydroxy and keto group and the amino and keto group in the crystalline state. The length of the polymethine chain, the nature of the substituents in the aromatic and aliphatic part of the molecule do not significantly affect the size and geometry of the alkylamino-β-ketoenolate fragment. Approximately the same lengths of bonds, the distance between atoms and the corners indicate that all these com-pounds may have similar chelating properties. Ac-cording to 1H NMR spectroscopy in various deu-terated solvents (benzene, DMSO, chloroform, ace-tone, methanol and trifluoroacetic acid), most of the main signals of the obtained compounds have sa-tellites, which indicates the existence of several isomeric forms in solutions. The analysis of integral intensities of labile protons in 1H NMR spectra does not allow to obtain accurate results regarding the ratio of tautomers in a solution, but for a series of compounds their approximate ratio in chloroform, DMSO and trifluoroacetic acid have been established (from 70:30 in CDCl3 to 90:10 in DMSO and CF3CO2D). The stability of the tautomers in the solutions is confirmed by the data of chromatogra-phy-mass spectrometry.

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Design of functionalized β-ketoenole derivatives as efficient fluorescent dyes for detection of amyloid fibrils

Abstract: Functionalized β-ketoenoles for efficient fluorescence sensing of protein amyloid fibrils giving strong emission increase up to 0.5 QY are designed.

Cited by 17 publications

References 36 publications

Structure and Aggregation Mechanisms in Amyloids

Structure and Aggregation Mechanisms in Amyloids

Modification of insulin amyloid aggregation by Zr phthalocyanines functionalized with dehydroacetic acid derivatives

CRYSTAL STRUCTURE AND TAUTOMERISM OF ALKYLAMINO-β-KETOENOLS IN SOLUTIONS

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