Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced autophagy activity against Alzheimer’s disease

Wei, Shenqi; Chen, Wei; Qin, Jingfang; Huangli, Yingzi; Wang, Li; Shen, Yue; Tang, Huang

doi:10.1016/j.bmc.2016.09.061

Cited by 13 publications

(13 citation statements)

References 35 publications

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“…The introduction of substituents on the 8‐ and 11‐positions results in better AChE inhibitory capacity than those of 6‐ and 10‐substituted derivatives, but weaker than that of 9‐substituted derivatives …”

Section: Structure–activity Relationships (Sars)mentioning

confidence: 99%

“…3) The introductiono fs ubstituents on the 8-and 11-positions results in betterA ChE inhibitory capacity than those of 6and 10-substituted derivatives, but weaker than that of 9substituted derivatives. [48] 4) Substitution on the 4-position results in better AChE inhibition activity than that of the 3-position. [4]…”

Section: Effects Of the Position Of The Side Chainmentioning

confidence: 99%

“…The reason for these results might be that the side chain with substitution at the 9‐ and 10‐positions could enter the active site of AChE. The 6‐substituted derivatives, nevertheless, possess a spatial orientation that is completely different from the 9‐ and 10‐subtituted derivatives; thus the terminal end group cannot enter the active site of the enzyme, thereby decreasing its inhibitory capacity. The introduction of substituents on the 8‐ and 11‐positions results in better AChE inhibitory capacity than those of 6‐ and 10‐substituted derivatives, but weaker than that of 9‐substituted derivatives Substitution on the 4‐position results in better AChE inhibition activity than that of the 3‐position …”

Section: Structure–activity Relationships (Sars)mentioning

confidence: 99%

“…Wei et al. synthesized 8‐ and 11‐substituted analogues (Figure ), with similar in vitro and in vivo AChE and Aβ aggregation inhibition abilities. In particular, compound 56 b ( n =2) showed IC 50 values reaching 28.4 n m and an inhibitory rate of up to 74.6 %.…”

Section: Structure Modificationmentioning

confidence: 99%

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Oxoisoaporphine Alkaloids: Prospective Anti‐Alzheimer's Disease, Anticancer, and Antidepressant Agents

2018

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Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and β-amyloid inhibition, acting as a topoisomerase intercalator, monoamine oxidase A inhibition, and are expected to become anti-Alzheimer's disease, anticancer, and antidepressant drugs. This review provides an overview of natural sources, synthetic routes, bioactivities, structure-function relationship, and modification investigations into oxoisoaporphine alkaloids, with the aim of providing references to the structure-activity relationships for the design and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential.

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Section: Structure–activity Relationships (Sars)mentioning

confidence: 99%

Section: Effects Of the Position Of The Side Chainmentioning

confidence: 99%

Section: Structure–activity Relationships (Sars)mentioning

confidence: 99%

Section: Structure Modificationmentioning

confidence: 99%

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Oxoisoaporphine Alkaloids: Prospective Anti‐Alzheimer's Disease, Anticancer, and Antidepressant Agents

2018

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“…Drugs in clinical trials that decrease the levels of Ab 42 have been proposed to be linked to a reduced risk of the AD development (see, for example, refs. [36][37][38][39][40][41] ). Various experimental studies have shown that Ab 42 possesses an increased toxicity in comparison with other Ab segments.…”

Section: Introductionmentioning

confidence: 99%

How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-β₄₂in water

Coskuner‐Weber

Uversky

2017

Intrinsically Disordered Proteins

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Amyloid-β (Aβ) is an intrinsically disordered peptide intimately related to the pathogenesis of several neurodegenerative diseases. Molecular dynamics (MD) simulations are extensively utilized in the characterization of the structures and conformational dynamics of intrinsically disordered proteins (IDPs) including Aβ, with AMBER and CHARMM parameters being commonly used in these studies. Recently, comparison of the effects of force field parameters on the Aβ structures has started to gain significant attention. In this study, the structures of Aβ are simulated using AMBER FF99SB and CHARMM22/CMAP parameters via replica exchange MD simulations utilizing a widely used clustering algorithm. These analyses show that the structural properties (extent and positioning of the elements of secondary and tertiary structure), radius of gyration values, number and position of salt bridges are extremely dependent on the chosen force field parameters notably with the usage of clustering algorithms. For example, predicted secondary structure elements, which are of the great importance for better understanding of the molecular mechanisms of neurodegenerative diseases, deviate enormously in models generated using currently available force field parameters for proteins. Based on the derived models, chemical shift values are calculated and compared to the experimentally determined data. This comparison revealed that although both force field parameters yield results in agreement with experiments, the obtained structural properties were rather different using a clustering algorithm. In other words, these results show that the predicted structures depend heavily on the force field parameters. Importantly, since none of the force field parameters currently utilized in MD studies were developed specifically taking into account the disordered nature of IDPs, these findings clearly indicate that new force field parameters have to be developed for IDPs considering their rapid flexibility and dynamics with high amplitude. Furthermore, molecular simulations of IDPs are typically conducted using one water volume. We show that the confined aqueous volume impacts the predicted structural properties of Aβ in water. Although up to date, confined aqueous volume effects have been ignored in the MD simulations of IDPs in water, our data indicate that these effects have to be taken into account in predicting the structural and thermodynamic properties of disordered proteins in solution.

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Design of Multi-target Directed Ligands as a Modern Approach for the Development of Innovative Drug Candidates for Alzheimer’s Disease

Ortiz

Silva

Gontijo

et al. 2018

Methods in Pharmacology and Toxicology

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Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced autophagy activity against Alzheimer’s disease

Cited by 13 publications

References 35 publications

Oxoisoaporphine Alkaloids: Prospective Anti‐Alzheimer's Disease, Anticancer, and Antidepressant Agents

Oxoisoaporphine Alkaloids: Prospective Anti‐Alzheimer's Disease, Anticancer, and Antidepressant Agents

How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-β₄₂in water

Design of Multi-target Directed Ligands as a Modern Approach for the Development of Innovative Drug Candidates for Alzheimer’s Disease

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Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced autophagy activity against Alzheimer’s disease

Cited by 13 publications

References 35 publications

Oxoisoaporphine Alkaloids: Prospective Anti‐Alzheimer's Disease, Anticancer, and Antidepressant Agents

Oxoisoaporphine Alkaloids: Prospective Anti‐Alzheimer's Disease, Anticancer, and Antidepressant Agents

How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-β42in water

Design of Multi-target Directed Ligands as a Modern Approach for the Development of Innovative Drug Candidates for Alzheimer’s Disease

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Product

Resources

About

How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-β₄₂in water