Tetrahydrocurcumin Derivatives Enhanced the Anti-Inflammatory Activity of Curcumin: Synthesis, Biological Evaluation, and Structure-Activity Relationship Analysis.

Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.

Polyphenols with Anti-Inflammatory Properties: Synthesis and Biological Activity of Novel Curcumin Derivatives.

Herein, we describe the synthesis and evaluation of anti-inflammatory activities of new curcumin derivatives. The thirteen curcumin derivatives were synthesized by Steglich esterification on one or both of the phenolic rings of curcumin with the aim of providing improved anti-inflammatory activity. Monofunctionalized compounds showed better bioactivity than the difunctionalized derivatives in terms of inhibiting IL-6 production, and known compound 2 presented the highest activity. Additionally, this compound showed strong activity against PGE2. Structure-activity relationship studies were carried out for both IL-6 and PGE2, and it was found that the activity of this series of compounds increases when a free hydroxyl group or aromatic ligands are present on the curcumin ring and a linker moiety is absent. Compound 2 remained the highest activity in modulating IL-6 production and showed strong activity against PGE2 synthesis.

Pouteria sapota (Red Mamey Fruit): Chemistry and Biological Activity of Carotenoids.

BACKGROUND: Red mamey is the fruit of P. sapota, a tree found in Mesoamerica and Asia. This fruit is considered a nutraceutical due to its multiple beneficial health including antiamyloidogenic activity and potential anti-tumorigenic property. Red mamey contain a variety of carotenoids including novel ketocarotenoids such as sapotexanthin and cryptocapsin. A ketocarotenoid is a chemical compound with a carbonyl group present in the ß-ring or in the double bond chain of a carotenoid. In red mamey, the 3'-deoxy-k-end group in sapotexanthin has proven to be an important pro-vitamin A source, which is essential for maintaining a healthy vision and cognitive processes. OBJECTIVE: This work reviews the current knowledge about the chemistry and biological activities of carotenoids in red mamey. METHOD: An exhaustive extraction is the most usual methodology to isolate and thoroughly characterize the carotenoids present in this fruit. High performance liquid chromatography is used to determine the profile of total carotenoids and its purity, while atmospheric pressure chemical ionization was used to determine their molecular weight and nuclear magnetic resonance determined their structure. RESULT: For each 100 g of fresh weight, 0.12 mg of total carotenoid from this fruit can be obtained. Out of the more than 47 reported carotenoids in red mamey, only 34 have a detailed characterization. CONCLUSION: It is important to continue studying the chemical composition and biological activity of this unique tropical fruit with commercial and nutritional value.

ß-glucans: wide-spectrum immune-balancing food-supplement-based enteric (ß-WIFE) vaccine adjuvant approach to COVID-19.

Conventional vaccines to combat COVID-19 through different approaches are at various stages of development. The complexity of COVID-19 such as the potential mutations of the virus leading to antigenic drift and the uncertainty on the duration of the immunity induced by the vaccine have hampered the efforts to control the COVID-19 pandemic. Thus, we suggest an alternative interim treatment strategy based on biological response modifier glucans such as the Aureobasidium pullulans AFO-202-derived ß-glucan, which has been reported to induce trained immunity, akin to that induced by the Bacille Calmette-Guérin vaccine, by epigenetic modifications at the central level in the bone marrow. These ß-glucans act as pathogen-associated molecular patterns, activating mucosal immunity by binding with specific pathogen recognition receptors such as dectin-1 and inducing both the adaptive and innate immunity by reaching distant lymphoid organs. ß-Glucans have also been used as immune adjuvants for vaccines such as the influenza vaccine. Therefore, until a conventional vaccine is widely available, an orally consumable vaccine adjuvant that acts like biosimilars, termed as the wide-spectrum immune-balancing food-supplement-based enteric (ß-WIFE) vaccine adjuvant approach, with well-reported safety is worth in-depth investigation and can be considered for a clinical trial.

Computational Evaluation of Interaction Between Curcumin Derivatives and Amyloid-ß Monomers and Fibrils: Relevance to Alzheimer's Disease.

BACKGROUND: The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-ß (Aß) fibrils due to the misfolding/aggregation of the Aß peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aß42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties. OBJECTIVE: To computationally assess the interaction between Aß peptide and a set of curcumin derivatives previously explored in experimental assays. METHODS: The interactions of ten ligands with Aß monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the Aß42 peptide, both in the monomeric and fibril forms. RESULTS: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aß42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aß42 monomers occur in a region critical for peptide aggregation. CONCLUSION: Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aß monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.

Polyphenols as Potential Metal Chelation Compounds Against Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-ß (Aß) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-ß protein precursor (AßPP) and Aß42 peptide, affecting Aß aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.

Reproducible molecular networking of untargeted mass spectrometry data using GNPS.

Global Natural Product Social Molecular Networking (GNPS) is an interactive online small molecule-focused tandem mass spectrometry (MS2) data curation and analysis infrastructure. It is intended to provide as much chemical insight as possible into an untargeted MS2 dataset and to connect this chemical insight to the user's underlying biological questions. This can be performed within one liquid chromatography (LC)-MS2 experiment or at the repository scale. GNPS-MassIVE is a public data repository for untargeted MS2 data with sample information (metadata) and annotated MS2 spectra. These publicly accessible data can be annotated and updated with the GNPS infrastructure keeping a continuous record of all changes. This knowledge is disseminated across all public data; it is a living dataset. Molecular networking-one of the main analysis tools used within the GNPS platform-creates a structured data table that reflects the molecular diversity captured in tandem mass spectrometry experiments by computing the relationships of the MS2 spectra as spectral similarity. This protocol provides step-by-step instructions for creating reproducible, high-quality molecular networks. For training purposes, the reader is led through a 90- to 120-min procedure that starts by recalling an example public dataset and its sample information and proceeds to creating and interpreting a molecular network. Each data analysis job can be shared or cloned to disseminate the knowledge gained, thus propagating information that can lead to the discovery of molecules, metabolic pathways, and ecosystem/community interactions.

Isolation and identification of sapotexanthin 5,6-epoxide and 5,8-epoxide from red mamey (Pouteria sapota).

Two new carotenoids, sapotexanthin 5,6-epoxide and sapotexanthin 5,8-epoxide, have been isolated from the ripe fruits of red mamey (Pouteria sapota). Sapotexanthin 5,6-epoxide was also prepared by partial synthesis via epoxidation of sapotexanthin, and the (5R,6S) and (5S,6R) stereoisomers were identified by high-performance liquid chromatography-electronic circular dichroism (HPLC-ECD) analysis. Spectroscopic data of the natural and semisynthetic derivatives obtained by acid-catalyzed rearrangement of cryptocapsin 5,8-epoxide stereoisomers were compared for structural elucidation.

Carotenoids as Novel Therapeutic Molecules Against Neurodegenerative Disorders: Chemistry and Molecular Docking Analysis.

Alzheimer's disease (AD) is the most devastating neurodegenerative disorder that affects the aging population worldwide. Endogenous and exogenous factors are involved in triggering this complex and multifactorial disease, whose hallmark is Amyloid-ß (Aß), formed by cleavage of amyloid precursor protein by ß- and γ-secretase. While there is no definitive cure for AD to date, many neuroprotective natural products, such as polyphenol and carotenoid compounds, have shown promising preventive activity, as well as helping in slowing down disease progression. In this article, we focus on the chemistry as well as structure of carotenoid compounds and their neuroprotective activity against Aß aggregation using molecular docking analysis. In addition to examining the most prevalent anti-amyloidogenic carotenoid lutein, we studied cryptocapsin, astaxanthin, fucoxanthin, and the apocarotenoid bixin. Our computational structure-based drug design analysis and molecular docking simulation revealed important interactions between carotenoids and Aß via hydrogen bonding and van der Waals interactions, and shows that carotenoids are powerful anti-amyloidogenic molecules with a potential role in preventing AD, especially since most of them can cross the blood-brain barrier and are considered nutraceutical compounds. Our studies thus illuminate mechanistic insights on how carotenoids inhibit Aß aggregation. The potential role of carotenoids as novel therapeutic molecules in treating AD and other neurodegenerative disorders are discussed.

Anti-amyloid aggregation activity of novel carotenoids: implications for Alzheimer's drug discovery.

Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6-epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Aß aggregation: by preventing the formation of the fibril and through disruption of the Aß aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti-amyloidogenic potential and could be used for prevention and treatment of AD.

Assessment of Novel Curcumin Derivatives as Potent Inhibitors of Inflammation and Amyloid-ß Aggregation in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity.

Mechanistic insights into the potassium tert-butoxide-mediated synthesis of N-heterobiaryls.

We report herein that symmetrical and non-symmetrical N-heterobiaryls are produced by a potassium tert-butoxide-mediated dimerization of heterocyclic N-oxides. The reaction is scalable and transition metal-free, and can be carried out under thermal and microwave conditions. Preliminary mechanistic studies point to the involvement of radical anionic intermediates arising from the N-oxide substrates and potassium tert-butoxide.

Experimental and mechanistic analysis of the palladium-catalyzed oxidative C8-selective C-H homocoupling of quinoline N-oxides.

A novel site-selective palladium-catalyzed oxidative C8-H homocoupling reaction of quinoline N-oxides has been developed. The reaction affords substituted 8,8'-biquinolyl N,N'-dioxides that can be readily converted to a variety of functionalized 8,8'-biquinolyls. Mechanistic studies point to the crucial role of the oxidant and a non-innocent behavior of acetic acid as a solvent.

Palladium-Catalyzed C8-Selective C-H Arylation of Quinoline N-Oxides: Insights into the Electronic, Steric and Solvation Effects on the Site-Selectivity by Mechanistic and DFT Computational Studies.

We report herein a palladium-catalyzed C-H arylation of quinoline N-oxides that proceeds with high selectivity in favor of the C8-isomer. This site-selectivity is unusual for palladium, since all of the hitherto described methods of palladium-catalyzed C-H functionalization of quinoline N-oxides are highly C2-selective. The reaction exhibits a broad synthetic scope with respect to quinoline N-oxides and iodoarenes and can be significantly accelerated to sub-hour reaction times under microwave irradiation. The C8-arylation method can be carried out on gram scale and has excellent functional group tolerance. Mechanistic and Density Functional Theory (DFT) computational studies provide evidence for the cyclopalladation pathway and describe key parameters influencing the site-selectivity.

Polyphenols as therapeutic molecules in Alzheimer's disease through modulating amyloid pathways.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative condition. The complex pathology of this disease includes oxidative stress, metal deposition, formation of aggregates of amyloid and tau, enhanced immune responses, and disturbances in cholinesterase. Drugs targeted toward reduction of amyloidal load have been discovered, but there is no effective pharmacological treatment for combating the disease so far. Natural products have become an important avenue for drug discovery research. Polyphenols are natural products that have been shown to be effective in the modulation of the type of neurodegenerative changes seen in AD, suggesting a possible therapeutic role. The present review focuses on the chemistry of polyphenols and their role in modulating amyloid precursor protein (APP) processing. We also provide new hypotheses on how these therapeutic molecules may modulate APP processing, prevent Aß aggregation, and favor disruption of preformed fibrils. Finally, the role of polyphenols in modulating Alzheimer's pathology is discussed.