Novel multi-target compounds in the quest for new chemotherapies against Alzheimer’s disease: An experimental and theoretical study

Martínez, Alberto; Zahran, Mai; Gómez, Miguel Ángel Sánchez; Cooper, Coreen; Guevara, Johnny; Ekengard, Erik; Nordlander, Ebbe; Alcendor, Ralph; Hambleton, Sarah

doi:10.1016/j.bmc.2018.08.019

Cited by 16 publications

(13 citation statements)

References 80 publications

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“…Five resveratrol oligomers isolated from the stembark extract of Vitis vinifera [39] along with eleven resveratrol oligomers, isolated from the seed extract of Paeonia lactiflora (Paeoniaceae) [40], were reported to inhibit baculovirus-expressed BACE 1 activity in a dose dependent manner. Such activity was recently confirmed in a homogeneous time-resolved fluorescence (TRF) assay [41], showing an inhibitory activity with an IC50 of 28 mM. Similarly, gnetin C, a resveratrol dimer (5-100 µM), was reported to suppress BACE 1 expression in SH-SY5Y cells, to reduce Aβ42 production and to ameliorate Aβ42-lowered cell viability [42].…”

Section: β-Secretasementioning

confidence: 82%

Wine Polyphenols and Neurodegenerative Diseases: An Update on the Molecular Mechanisms Underpinning Their Protective Effects

Silva

Vauzour

2018

Beverages

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Alzheimer's and Parkinson's diseases are the most common age-related and predominantly idiopathic neurodegenerative disorders of unknown pathogenesis. Although these diseases differ in their clinical and neuropathological features, they also share some common aetiologies, such as protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Epidemiological, in vitro and in vivo evidences suggest an inverse correlation between wine consumption and the incidence of neurodegenerative disorders. Wine benefits are, in large part, attributable to the intake of specific polyphenols, which mediate cell function under both normal and pathological conditions. In this review, we aim to provide an overview of the role that wine polyphenols play in delaying neurodegenerative disorders. We discuss animal and in vitro studies in support of these actions and we consider how their biological mechanisms at the cellular level may underpin their physiological effects. Together, these data indicate that polyphenols present in wine may hold neuroprotective potential in delaying the onset of neurodegenerative disorders.

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Section: β-Secretasementioning

confidence: 82%

Wine Polyphenols and Neurodegenerative Diseases: An Update on the Molecular Mechanisms Underpinning Their Protective Effects

Silva

Vauzour

2018

Beverages

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“…The chelation ability of compound 6b 1 toward biometals such as Na + , K + , Cu 2+ , Fe 2+ , Mg 2+ , Ca 2+ , and Zn 2+ was studied by UV-vis spectrometry [47,48]. When Cu 2+ , Fe 2+ , and Zn 2+ was added, new optical bands were observed at about 498 nm, and the peak at about 393.5 nm which was observed on UV spectrum of compound 6b 1 in ethanol alone decreased, indicative of the interaction between Cu 2+ , Fe 2+ , Zn 2+ and compound 6b 1 to form the complex 6b 1 -metal (Ⅱ).…”

Section: Resultsmentioning

confidence: 99%

“…The metal chelation of compound 6b 1 was tested in ethanol using a UV-vis spectrophotometer (Shimadzu UV-2450PC) with wavelength ranging from 200 to 700 nm [47,48]. The absorption spectra of compound 6b 1 (10 μM, final concentration) alone or in the presence of metal ions (20 μM, final concentration) after incubation for 30 min at room temperature, was recorded at room temperature in a 1 cm quartz cell.…”

Section: Methodsmentioning

confidence: 99%

Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-Target Agents for the Treatment of Alzheimer’s Disease

et al. 2018

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Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series of 4-flexible amino-2-arylethenylquinoline derivatives as multi-target agents was efficiently synthesized and evaluated for the treatment of AD. Among these synthesized derivatives, some compounds exhibited strong self-induced Aβ1–42 aggregation inhibition and antioxidant activity. The structure-activity relationship was summarized, which confirmed that the introduction of a flexible amino group featuring a N,N-dimethylaminoalkylamino moiety at the 4-position increased the Aβ1–42 aggregation inhibition activity, with an inhibition ratio of 95.3% at 20 μM concentration. Compound 6b1, the optimal compound, was able to selectively chelate copper (II), and inhibit Cu2+-induced Aβ aggregation effectively. It also could disassemble the self-induced Aβ1–42 aggregation fibrils with a ratio of 64.3% at 20 μM concentration. Moreover, compound 6b1 showed low toxicity and a good neuroprotective effect against Aβ1–42-induced toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated compound 6b1 significantly reversed scopolamine-induced memory deficit in mice. Taken together, these results suggested that compound 6b1 was a promising multi-target compound worthy of further study for AD.

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“…Given that AD is a multifactor‐associated disease, in short future, multifunctional drugs, which produce the synergistic effect by regulating several therapeutic targets concurrently, might lead to a breakthrough in AD treatment. Other groups and our group have designed and synthesized a series of novel multifunctional compounds targeting BACE 1, Aβ, Cu 2+ metal ions and/or ROS production . An ideal sAD animal model might be the critical approach for the R&D of multifunctional anti‐AD drugs.…”

Section: Nhps: a Bridge Between Rodents And Humans?mentioning

confidence: 99%

“…Other groups and our group have designed and synthesized a series of novel multifunctional compounds targeting BACE 1, Aβ, Cu 2+ metal ions and/or ROS production. [173][174][175][176] An ideal sAD animal model might be the critical approach for the R&D of multifunctional anti-AD drugs.…”

Section: Perspectivementioning

confidence: 99%

Advance of sporadic Alzheimer's disease animal models

Zhang

Chen

Mak

et al. 2019

Medicinal Research Reviews

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Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disease. In the past decades, numbers of promising drug candidates showed significant anti‐AD effects in preclinical studies but failed in clinical trials. One of the major reasons might be the limitation of appropriate animal models for evaluating anti‐AD drugs. More than 95% of AD cases are sporadic AD (sAD). However, the anti‐AD drug candidates were mainly tested in the familial AD (fAD) animal models. The diversity between the sAD and fAD might lead to a high failure rate during the development of anti‐AD drugs. Therefore, an ideal sAD animal model is urgently needed for the development of anti‐AD drugs. Here, we summarized the available sAD animal models, including their methodology, pathologic features, and potential underlying mechanisms. The limitations of these sAD animal models and future trends in the field were also discussed.

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Novel multi-target compounds in the quest for new chemotherapies against Alzheimer’s disease: An experimental and theoretical study

Cited by 16 publications

References 80 publications

Wine Polyphenols and Neurodegenerative Diseases: An Update on the Molecular Mechanisms Underpinning Their Protective Effects

Wine Polyphenols and Neurodegenerative Diseases: An Update on the Molecular Mechanisms Underpinning Their Protective Effects

Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-Target Agents for the Treatment of Alzheimer’s Disease

Advance of sporadic Alzheimer's disease animal models

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