Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor

Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

doi:10.1016/j.bmcl.2014.10.076

Cited by 43 publications

(24 citation statements)

References 27 publications

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“…Small molecule inhibitors were reported to directly or indirectly alter the aggregation pathways. The inhibitors can be small chemical compounds directly binding to Aβ or metal ion chelators to block Aβ-metal interaction[39–41]. Direct binding of the compounds may change Aβ conformation or block Aβ association to prevent aggregation.…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity

Lin

Chang

et al. 2017

PLoS ONE

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Alzheimer’s disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-β peptide (Aβ). Several familial mutations found in Aβ sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Aβ, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Aβ shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Aβ40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Aβ, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibition effect of various N-terminal fragments (NTFs) of A2T to WT Aβ. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Aβ fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or specific N-terminal A2T can retard Aβ aggregation and the A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD.

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Section: Introductionmentioning

confidence: 99%

Alzheimer’s amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity

Lin

Chang

et al. 2017

PLoS ONE

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“…Although several Aβ aggregation inhibitors have been reported, still, the interaction between Aβ and its inhibitors is unclear. The phenolic groups present in the novel compounds such as curcumin can interact with the aromatic residues in amyloid fibrils unsettling peptide π–π piling whereas the hydroxyl groups can play the role of β‐sheet breakers through competitive hydrogen bonding . Nonetheless, this mechanism is still partly explained which can be attributed to the difficulty in handling Aβ which has self‐cohesive properties, poor water solubility, and is non‐crystalline …”

Section: Resultsmentioning

confidence: 99%

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

et al. 2016

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Neurodegeneration, a complex disease state, comprises several pathways that contribute to cell death. Conventional approach of targeting only one of these pathways has not been proven to be entirely successful and has demanded a hypothetical change as to how researchers design and develop new drugs. In this study, effects of a series of α, β-unsaturated carbonyl-based tetralone derivatives against Alzheimer's disease (AD) were investigated. Moreover, their activity toward amyloid β-induced cytotoxicity was also studied. Six compounds including 3f, 3o, 3u, 3ae, 3af, and 3ag were discovered to be most protective against Aβ-induced neuronal cell death in PC12 cells. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against MAO-B, AChE, and self-induced Aβ aggregation. The compound 3f exhibited best AChE (IC = 0.045 ± 0.02 μm) inhibitory potential in addition to potent inhibition of MAO-B (IC = 0.88 ± 0.12 μm). Furthermore, compound 3f disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 78.2 ± 4.8%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment.

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“…Hitoshi Endo et al [53] found that AB18 is the ideal in vitro amyloid-β aggregation inhibitor among synthesized curcumin analogues. AB18 also has water solubility that is 160 times higher than curcumin.…”

Section: In Vitromentioning

confidence: 99%

“…for the development of potential theranostic agents (both diagnostic and therapeutic) for neurodegenerative diseases (Figure 1 and Table 2). The bivalent ligand AB69, with its spacer (length of 17 atoms) formed a complex with biometals, such as Cu, Fe, and Zn to provide new analogues with novel pharmacological activity and potency ( Figure 11 and Table 2) [53].…”

Section: Inhibition Of Achementioning

confidence: 99%

Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids

Chainoglou

Hadjipavlou‐Litina

2020

IJMS

109

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Worldwide, Alzheimer’s disease (AD) is the most common neurodegenerative multifactorial disease influencing the elderly population. Nowadays, several medications, among them curcumin, are used in the treatment of AD. Curcumin, which is the principal component of Curcuma longa, has shown favorable effects forsignificantly preventing or treating AD. During the last decade, the scientific community has focused their research on the optimization of therapeutic properties and on the improvement of pharmacokinetic properties of curcumin. This review summarizes bibliographical data from 2009 to 2019 on curcumin analogues, derivatives, and hybrids, as well as their therapeutic, preventic, and diagnostic applications in AD. Recent advances in the field have revealed that the phenolic hydroxyl group could contribute to the anti-amyloidogenic activity. Phenyl methoxy groups seem to contribute to the suppression of amyloid-β peptide (Aβ42) and to the suppression of amyloid precursor protein (APP) andhydrophobic interactions have also revealed a growing role. Furthermore, flexible moieties, at the linker, are crucial for the inhibition of Aβ aggregation. The inhibitory activity of derivatives is increased with the expansion of the aromatic rings. The promising role of curcumin-based compounds in diagnostic imaging is highlighted. The keto-enol tautomerism seems to be a novel modification for the design of amyloid-binding agents. Molecular docking results, (Q)SAR, as well as in vitro and in vivo tests highlight the structures and chemical moieties that are correlated with specific activity. As a result, the knowledge gained from the existing research should lead to the design and synthesis ofinnovative and multitargetedcurcumin analogues, derivatives, or curcumin hybrids, which would be very useful drug and tools in medicine for both diagnosis and treatment of AD.

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Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor

Cited by 43 publications

References 27 publications

Alzheimer’s amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity

Alzheimer’s amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids

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