Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: The case of chelerythrine

Brunhofer, Gerda; Fallarero, Adyary; Karlsson, Daniela; Batista‐González, Ana; Shinde, Pravin V.; Mohan, C. Gopi; Vuorela, Pia

doi:10.1016/j.bmc.2012.09.040

Cited by 67 publications

(54 citation statements)

References 47 publications

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“…The indole alkaloids nitrarine, hirsutine, rauwolscine and catharanthine (Figure ) display BChE selective inhibition, with no significant difference between eqBChE and hBChE. The IC 50 values for eqBChE inhibition range from 4.97 to 10.6 μ m , while the IC 50 values for hBChE inhibition ranged from 1.97 to 13.7 μ m . These results suggest that the monoterpene side chain fused to the indole ring does not critically influence the potential for BChE inhibition.…”

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 89%

“…This binding mode represents an interesting feature, since it is possible to assume an additional capacity to target the AChE‐induced Aβ aggregation process. Further experiments demonstrated that chelerythrine at 5, 10 and 100 μ m is able to inhibit the AChE‐induced Aβ fibrillogenesis in a concentration‐dependent way reaching almost 90% of inhibition at the highest concentration …”

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 97%

“…Additionally, the effects of the alkaloids from S. venosa on Ee AChE were compared with those displayed by the well‐known quaternary alkaloids berberine ( Ee AChE IC 50 = 0.58 μ m ), palmatine ( Ee AChE IC 50 = 0.26 μ m ) and jatrorrhizine (IC 50 = 0.93 μ m ). Besides Ee AChE, berberine and palmatine were also tested in human, mice and rat enzymes displaying about the same potency . Regarding BChE, both compounds inhibited equine serum enzymes, displaying IC 50 values corresponding to 3.44 and 6.84 μ m , respectively …”

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 99%

“…Kinetic studies indicated that it acts as a mixed inhibitor of Ee AChE and human AChE (hAChE) with a competitive behaviour. Considering this mode of inhibition, Brunhofer et al . suggested that chelerythrine could bind to the peripheral anionic site (PAS).…”

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 99%

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Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Konrath

Passos

Klein‐Júnior

et al. 2013

Journal of Pharmacy and Pharmacology

172

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Objectives The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl-and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies. Key findings Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors. Summary The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD.

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Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 89%

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 97%

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 99%

Section: Classes Of Anticholinesterase Alkaloidsmentioning

confidence: 99%

See 2 more Smart Citations

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Konrath

Passos

Klein‐Júnior

et al. 2013

Journal of Pharmacy and Pharmacology

172

View full text Add to dashboard Cite

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“…The inhibition of MRCKα by chelerythrine was not affected by raising the ATP concentration as much as 20-fold higher, indicating that the mode of inhibition was unlikely to be via ATP-competition. A lack of selectivity makes chelerythrine difficult to use for cell-based or in vivo experiments to evaluate MRCK function, additional reported off-target effects include reactive oxygen species generation [29], DNA intercalation [30] and inhibition of acetylcholinesterases [31]. By coupling the AKT inhibitor GSK690693 to solid substrates to facilitate purification of interacting proteins, MRCKβ was identified as a major interacting protein [32].…”

Section: Mrck Inhibitorsmentioning

confidence: 99%

The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

Unbekandt

Olson

2014

J Mol Med

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The contractile actin-myosin cytoskeleton provides much of the force required for numerous cellular activities such as motility, adhesion, cytokinesis and changes in morphology. Key elements that respond to various signal pathways are the myosin II regulatory light chains (MLC), which participate in actin-myosin contraction by modulating the ATPase activity and consequent contractile force generation mediated by myosin heavy chain heads. Considerable effort has focussed on the role of MLC kinases, and yet the contributions of the myotonic dystrophy-related Cdc42-binding kinases (MRCK) proteins in MLC phosphorylation and cytoskeleton regulation have not been well characterized. In contrast to the closely related ROCK1 and ROCK2 kinases that are regulated by the RhoA and RhoC GTPases, there is relatively little information about the CDC42-regulated MRCKα, MRCKβ and MRCKγ members of the AGC (PKA, PKG and PKC) kinase family. As well as differences in upstream activation pathways, MRCK and ROCK kinases apparently differ in the way that they spatially regulate MLC phosphorylation, which ultimately affects their influence on the organization and dynamics of the actin-myosin cytoskeleton. In this review, we will summarize the MRCK protein structures, expression patterns, small molecule inhibitors, biological functions and associations with human diseases such as cancer.

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Inhibition of protein misfolding and aggregation by natural phenolic compounds

Dhouafli

Cuanalo-Contreras

Hayouni

et al. 2018

Cell. Mol. Life Sci.

121

115

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Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer's and Parkinson's diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.

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Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: The case of chelerythrine

Cited by 67 publications

References 47 publications

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease

The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

Inhibition of protein misfolding and aggregation by natural phenolic compounds

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