Clicked" sugar-curcumin conjugate: modulator of amyloid-β and tau peptide aggregation at ultralow concentrations (original) (raw)
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ACS Chemical …, 2011
The synthesis of a water/plasma soluble, noncytotoxic, "clicked" sugar-derivative of curcumin with amplified bioefficacy in modulating amyloid-β and tau peptide aggregation is presented. Curcumin inhibits amyloid-β and tau peptide aggregation at micromolar concentrations; the sugar−curcumin conjugate inhibits Aβ and tau peptide aggregation at concentrations as low as 8 nM and 0.1 nM, respectively. In comparison to curcumin, this conveniently synthesized Alzheimer's drug candidate is a more powerful antioxidant.
Prenylated Curcumin Analogues as Multipotent Tools to Tackle Alzheimer's Disease
ACS Chemical Neuroscience
Alzheimer's disease is likely to be caused by copathogenic factors including aggregation of Aβ peptides into oligomers and fibrils, neuroinflammation and oxidative stress. To date, no effective treatments are available and because of the multifactorial nature of the disease, it emerges the need to act on different and simultaneous fronts. Despite the multiple biological activities ascribed to curcumin as neuroprotector, its poor bioavailability and toxicity limit the success in clinical outcomes. To tackle Alzheimer's disease on these aspects, the curcumin template was suitably modified and a small set of analogues was attained. In particular, derivative 1 turned out to be less toxic than curcumin. As evidenced by capillary electrophoresis and transmission electron microscopy studies, 1 proved to inhibit the formation of large toxic Aβ oligomers, by shifting the equilibrium towards smaller non-toxic assemblies and to limit the formation of insoluble fibrils. These findings were supported by molecular docking and steered molecular dynamics simulations which confirmed the superior capacity of 1 to bind Aβ structures of different complexity. Remarkably, 1 also showed in vitro anti-inflammatory and anti-oxidant properties. In summary, the curcumin-based analogue 1 emerged as multipotent compound worth to be further investigated and exploited in the Alzheimer's disease multi-target context.
INDONESIAN JOURNAL OF PHARMACY, 2022
Alzheimer's disease (AD) is a neurological illness that is known to cause a wide range of cognitive symptoms linked to amyloid plaque deposition, neurofibrillary tangles, oxidative stress, and neuronal death in the whole brain. Curcumin has shown promising efficacy in preclinical studies for AD treatment. However, it failed to exhibit expected clinical outcomes in clinical studies. Besides, this molecule was found to have low stability, solubility, and bioavailability properties. Hence, scientists have synthesized several curcumin analogues in order to improve their bioavailability and biological activity. In this narrative review, we aim to discuss the development of curcumin analogue synthesis published in 2016-2021 and its efficacy as an anti-Alzheimer's candidate through in vitro, cell-based, and in vivo studies. PubMed and Scopus database were searched using the keywords "curcumin" AND "analogues" OR "analogs" AND "Alzheimer's" to find relevant studies. In our review, we included 16 eligible journal articles to discuss. In total, 15 curcumin analogues exhibited promising efficacy in preclinical studies and are found suitable for anti-Alzheimer's candidates. Further studies should explore curcumin analogues' effectiveness in other AD subpathologies as well as its pharmacokinetic profile and ability to achieve target action in the brain.
Biomaterials, 2010
Curcumin, which can exist in an equilibrium between keto and enol tautomers, binds to b-amyloid (Ab) fibrils/aggregates. The aim of this study was to assess the relationship between the tautomeric structures of curcumin derivatives and their Ab-binding activities. Curcumin derivatives with keto-enol tautomerism showed high levels of binding to Ab aggregates but not to Ab monomers. The binding activity of the keto form analogue of curcumin to Ab aggregates was found to be much weaker than that of curcumin derivatives with keto-enol tautomerism. The color of a curcumin derivative with keto-enol tautomerism, which was substituted at the C-4 position, changed from yellow to orange within 30 min of being combined with Ab aggregates in physiological buffer. This resulted from a remarkable increase in the enol form with extended conjugation of double bonds upon binding. These findings suggest that curcumin derivatives exist predominantly in the enol form during binding to Ab aggregates, and that the enolization of curcumin derivatives is crucial for binding to Ab aggregates. The keto-enol tautomerism of curcumin derivatives may be a novel target for the design of amyloid-binding agents that can be used both for therapy and for amyloid detection in Alzheimer's disease.
Network Modeling Analysis in Health Informatics and Bioinformatics, 2013
Alzheimer's disease (AD) is caused by the accumulation of beta-amyloid (b-A) in the brain that forms amyloid plaque. b-A is an oligo-peptide consisting of 39-42 amino acid residues, produced by proteolytic cleavage of amyloid precursor protein by secretase enzymes. Evolutionary trace and protein family analysis of b-A indicates that C-terminal residues of b-A are highly conserved and hydrophobic in nature. Prevalence of hydrophobic residues at C-terminal of b-A promote aggregation, and also provide the stability to b-A plaque due to hydrophobic-hydrophobic interaction between residues of b-A. In this work, designing, evaluation and screening of potent inhibitors for b-A formation were studied. Curcumin and some of its herbal congeners were taken into consideration, to evaluate their anti-alzheimeric property against b-A as well as with b-A fibrils. Most of these herbal compounds were found potent inhibitors of b-A aggregation than known drugs for AD. The binding affinity of cassumunins A and B was compared with that of curcumin and it was found that cassumunins A and B may cause more potent inhibition of b-A than curcumin. Principal descriptors as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties for these compounds were predicted, and were found satisfactory.
Organic Letters, 2007
Curcumin, the primary active ingredient in the spice turmeric, was converted to reactive monofunctional derivatives (carboxylic acid/azide/ alkyne). The derivatives were employed to produce a 3 + 2 azide−alkyne "clicked" curcumin dimer and a poly(amidoamine) (PAMAM) dendrimer− curcumin conjugate. The monofunctional curcumin derivatives retain biological activity and are efficient for labeling and dissolving amyloid fibrils. The curcumin dimer selectively destroys human neurotumor cells. The synthetic methodology developed affords a general strategy for attaching curcumin to various macromolecular scaffolds.
Challenges associated with curcumin therapy in Alzheimer disease
Expert Reviews in Molecular Medicine, 2011
Curcumin, the phytochemical agent in the spice turmeric, which gives Indian curry its yellow colour, is also a traditional Indian medicine. It has been used for millennia as a wound-healing agent and for treating a variety of ailments. The antioxidant, anti-inflammatory, antiproliferative and other properties of curcumin have only recently gained the attention of modern pharmacology. The mechanism of action of curcumin is complex and multifaceted. In part, curcumin acts by activating various cytoprotective proteins that are components of the phase II response. Over the past decade, research with curcumin has increased significantly. In vitro and in vivo studies have demonstrated that curcumin could target pathways involved in the pathophysiology of Alzheimer disease (AD), such as the β-amyloid cascade, tau phosphorylation, neuroinflammation or oxidative stress. These findings suggest that curcumin might be a promising compound for the development of AD therapy. However, its insolubi...
Journal of Biological Chemistry, 2004
Alzheimer's disease (AD) involves amyloid  (A) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and antiinflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential A binding, we investigated whether its efficacy in AD models could be explained by effects on A aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC 50 ؍ 0.8 M) as well as disaggregated fibrillar A40 (IC 50 ؍ 1 M), indicating favorable stoichiometry for inhibition. Curcumin was a better A40 aggregation inhibitor than ibuprofen and naproxen, and prevented A42 oligomer formation and toxicity between 0.1 and 1.0 M. Under EM, curcumin decreased dose dependently A fibril formation beginning with 0.125 M. The effects of curcumin did not depend on A sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small -amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates A as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.
The Mechanisms of Action of Curcumin in Alzheimer’s Disease
Journal of Alzheimer's Disease, 2017
Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly. As the prevalence of AD rises in the 21st century, there is an urgent need for the development of effective pharmacotherapies. Currently, drug treatments target the symptoms of the disease and do not modify or halt the disease progress. Thus, natural compounds have been investigated for their ability to treat AD. This review examines the efficacy of curcumin, a polyphenol derived from turmeric herb, to treat AD. We summarize the in vivo and in vitro research describing the mechanisms of action in which curcumin modifies AD pathology: curcumin inhibits the formation and promotes the disaggregation of amyloid- plaques, attenuates the hyperphosphorylation of tau and enhances its clearance, binds copper, lowers cholesterol, modifies microglial activity, inhibits acetylcholinesterase, mediates the insulin signaling pathway, and is an antioxidant. In conclusion, curcumin has the potential to be more efficacious than current treatments. However, its usefulness as a therapeutic agent may be hindered by its low bioavailability. If the challenge of low bioavailability is overcome, curcumin-based medications for AD may be in the horizon.