Relationship between the tautomeric structures of curcumin derivatives and their Aβ-binding activities in the context of therapies for Alzheimer's disease

Yanagisawa, Daijiro; Shirai, Nobuyuki; Amatsubo, Tomone; Taguchi, Hiroyasu; Hirao, Koichi; Urushitani, Makoto; Morikawa, Shigehiro; Inubushi, Toshiro; Kato, Masanari; Kato, Fuminori; Morino, Kyuya; Kimura, Hirohiko; Nakano, ﻿Ichiro; Yoshida, Chikako; Okada, Takashi; Sano, Mitsuo; Wada, Yasuhiro; Wada, Kennosuke; Yamamoto, Akira; Tooyama, Ikuo

doi:10.1016/j.biomaterials.2010.01.142

Cited by 140 publications

(172 citation statements)

References 22 publications

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“…Moreover, curcumin has high affinity to Aβ 42 , oligomers, and fibrils, which are tightly linked to AD (62)(63)(64)(65)(66)(67)(68). Curcumin intensely stains the central dense amyloid core in Aβ fibrils and plaques, as was also previously demonstrated in the brain of murine models of AD (101).…”

Section: Discussionsupporting

confidence: 67%

“…To visualize retinal Aβ pathology in vivo, we had previously developed a noninvasive retinal amyloid imaging method for rodent ADtg models, using curcumin as a contrast agent (40,51). Curcumin is a natural and safe phytopolylphenol fluorochrome that binds to Aβ fibrils and oligomers with high affinity and specificity (62)(63)(64)(65)(66)(67)(68). This approach enabled noninvasive detection and monitoring of individual retinal Aβ deposits in live ADtg mice (40,51).…”

Section: Introductionmentioning

confidence: 99%

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Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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BACKGROUND. Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS.Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS.Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ 42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION.The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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“…Curcumin was reported to interact with A␤40 fibrils through the planarity of the enol form of curcumin (46). Also given are the preferable detection of monomeric A␤42 in LC-MS analysis, similar analysis was performed to clarify the interaction between A␤42 and (ϩ)-taxifolin.…”

Section: Inhibitory Effect Of (ϩ)-Taxifolin On Aggregation Of A␤42 Mumentioning

confidence: 99%

Site-specific Inhibitory Mechanism for Amyloid β42 Aggregation by Catechol-type Flavonoids Targeting the Lys Residues

Satô

Murakami²,

Uno³

et al. 2013

Journal of Biological Chemistry

208

227

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Background:The inhibitory mechanism of A␤42 aggregation by flavonoid is fully unknown. Results: The oxidant enhanced the inhibitory activity of (ϩ)-taxifolin against A␤42 aggregation by forming A␤42-taxifolin adducts between the Lys residues and oxidized (ϩ)-taxifolin. Conclusion:The inhibitory activity of catechol-type flavonoids requires autoxidation to form an o-quinone to react with Lys. Significance: These may help design promising inhibitors against A␤42 aggregation for Alzheimer disease therapy.

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“…The keto-enol isomeric effect on structural pharmacophore may play an important role in binding of this analog with drug target. The relationship between tautomeric structures of curcumin and its effect on neurodegenerative diseases like Alzheimer's was the research of interest for the present [18]. So the initial efforts were taken to study the effect of indole by synthesis of 6-aryl-5-hexene-2, 4-diones using 1H-indole-3-carboxaldehyde.…”

Section: Introductionmentioning

confidence: 99%

A STUDY ON EFFECT OF INDOLE AS a SUBSTITUENT ON a KETO-ENOL TAUTOMER: A SYNTHETIC APPROACH ON Β-Diketone

Krishnakumar¹,

Ukken

Manju

2017

Int J Pharm Pharm Sci

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Objective: The existence of keto-enol tautomerism in β-diketones can typically study by a choice of analytical technique. The position of the ketoenol equilibrium depends on a number of factors like solvent, temperature, and substituents. Here an attempt was made to examine the effect of indole, a heterocyclic moiety with the moderately high polar surface area to examine its effect on ketonisation of β-diketone. Methods:The β-diketone studied and synthesized is a structural analog of magical drug curcumin. The structural influence of indole on ketonisation of β-diketone is studied to give a hypothesis on factors contributing towards ketonisation. This work involves the synthesis of 6-(1H-Indol-3-yl)-hex-5ene-2, 4-dione and the study on the single crystal structure of indole-3-carboxaldehyde, major functional component to result in the reaction. The tautomer was studied for its ability to bind with tetrahydrofolate reductase enzyme using Discovery Studio 3.5 version to differentiate the pharmacological significance of conformations. Results:The single crystal XRD structure of this compound was deposited in Cambridge crystallographic data center bearing CCDC No.1536311. The structural characterization of synthesized ligand was carried out by using IR, Mass, 1 Conclusion:The experimental evidence proves that indole substitution shifted the keto-enol equilibrium towards keto form of 6-(1H-Indol-3-yl)-hex-5ene-2, 4-dione.H NMR spectroscopic techniques. The docking study reveals that keto isomer found to exhibit more inhibition of the enzyme tetrahydrofolate reductase hence more pharmacologically active.

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Relationship between the tautomeric structures of curcumin derivatives and their Aβ-binding activities in the context of therapies for Alzheimer's disease

Cited by 140 publications

References 22 publications

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Site-specific Inhibitory Mechanism for Amyloid β42 Aggregation by Catechol-type Flavonoids Targeting the Lys Residues

A STUDY ON EFFECT OF INDOLE AS a SUBSTITUENT ON a KETO-ENOL TAUTOMER: A SYNTHETIC APPROACH ON Β-Diketone

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