Castalagin
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Product Description
Castalagin is a rare, plant-derived C-glycosidic ellagitannin whose name is becoming almost synonymous with “oak tannin”: it is abundant in heartwood of Quercus, Castanea and Terminalia species, leaches into wine or spirits aged in oak barrels and, together with its C-1 diastereomer vescalagin, shapes their astringency, color and oxidative stability. Beyond flavour chemistry, castalagin is attracting intense biomedical interest. Pure compound and camu-camu–rich extracts display low-nanomolar antioxidant capacity, protect neuronal cells from amyloid-β42 oligomer toxicity by remodelling the peptide’s secondary structure, and suppress HSV-1 replication in vitro as effectively as acyclovir while retaining activity against ACV-resistant mutants; in newborn mice the selectivity index exceeds 30. In tropical medicine, castalagin is the principal leishmanicidal principle of Anogeissus leiocarpus bark (EC50 55–110 µg mL⁻¹ against four Leishmania strains), rationalizing an African ethnopharmacological use. Most recently, the tannin has been shown to reprogramme the gut microbiome, enriching bacteria that generate immune-stimulatory metabolites and thereby overcoming resistance to anti-PD-1 cancer immunotherapy. These diverse bioactivities, coupled with a favourable conformation that makes castalagin less polar and more thermostable than vescalagin, position the molecule as a versatile natural scaffold for neuroprotective, antiviral, antiparasitic and immuno-oncology applications.
Other Information
Natural Occurrence:
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Found in oak heartwood (Quercus spp.), chestnut wood (Castanea spp.), stem bark of Anogeissus leiocarpus and Terminalia avicennoides, and fruits like camu-camu (Myrciaria dubia).
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Major component in white wines aged in oak barrels (40-70% of total ellagitannins).
Derivatives and Related Compounds:
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Forms dimers (e.g., roburin A/D) and complexes with anthocyanins/flavonoids (e.g., acutissimin A).
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Hydrolyzes to vescalene and vescalin, which are potent topoisomerase II inhibitors.
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Glycosylated forms exist (e.g., grandinin).
Research Status:
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Multiple clinical trials are ongoing to investigate its role in enhancing immunotherapy and other therapeutic applications.
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Considered a promising candidate for developing lower-toxicity agents for bone diseases compared to conventional treatments like bisphosphonates.
Synthesis and Production
Natural Extraction and Isolation:
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Castalagin is primarily isolated from plant sources.
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The primary method involves an aqueous acetone extract of dried bark (e.g., from Castanea crenata or oak wood), followed by sequential column chromatography using Sephadex LH-20 and Diaion HP20SS with eluents of increasing methanol concentration.
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It is obtained as a white crystalline powder from water.
Biosynthesis:
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The biosynthetic pathway begins with 1,2,3,4,6-pentagalloyl-glucose.
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It proceeds via oxidative dehydrogenation to form intermediates like tellimagrandin II and casuarictin.
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Casuarictin is then converted to pedunculagin, which undergoes ring-opening of the glucose pyranose to ultimately yield castalagin and its diastereomer, vescalagin.
Uses and Applications
Medical and Therapeutic Applications:
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Cancer Immunotherapy Enhancement: Acts as a prebiotic that alters the gut microbiome, improving the efficacy of anti-PD-1 immunotherapy, particularly in non-small cell lung cancer (NSCLC) and melanoma. It increases the CD8+/FOXP3+CD4+ T-cell ratio in the tumor microenvironment.
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Bone Disease Treatment: Potently inhibits osteoclastogenesis (formation of bone-resorbing cells), suggesting potential use for osteoporosis, periodontitis, and rheumatoid arthritis.
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Antiviral Agent: Demonstrates marked virucidal effects against Herpes Simplex Virus type 1 (HSV-1).
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Antibacterial Agent: Shows bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and other bacteria, with potential for creating antibacterial biomaterials.
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Antiparasitic Agent: Exhibits powerful leishmanicidal activity.
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Antioxidant and Anti-inflammatory: General properties contribute to its therapeutic potential.
Industrial and Food Applications:
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Food and Beverage Industry: A key ellagitannin in oak-aged wines and spirits, contributing to color, taste, astringency, and aging transformations.
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Natural Product Source: Found in various botanicals used in traditional medicine and nutraceuticals.
Chemical and Physical Properties
Chemical Identity:
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IUPAC Name: (1R,2R,20R,42S,46R)-7,8,9,12,13,14,25,26,27,30,31,32,35,36,37,46-hexadecahydroxy-3,18,21,41,43-pentaoxanonacyclo[27.13.3.1³⁸,⁴².0²,²⁰.0⁵,¹⁰.0¹¹,¹⁶.0²³,²⁸.0³³,⁴⁵.0³⁴,³⁹]hexatetraconta-5,7,9,11,13,15,23,25,27,29(45),30,32,34(39),35,37-pentadecaene-4,17,22,40,44-pentone
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Molecular Formula: C₄₁H₂₆O₂₆
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Molecular Weight: 934.6 g/mol
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CAS Number: 36001-47-5; 24312-00-3
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Classification: Hydrolyzable tannin, Ellagitannin, Polyphenol
Structural Features:
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Complex, cage-like structure with nine interconnected rings.
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Contains 16 hydroxyl groups, 5 ketone groups, and multiple ether linkages.
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Open-chain glucose core esterified with hexahydroxydiphenoyl (HHDP) and nonahydroxytriphenoyl (NHTP) groups.
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Diastereomer of vescalagin (differs in stereochemistry at one carbon).
Physicochemical Properties:
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Appearance: White crystalline powder or yellow-brown amorphous solid.
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Solubility: Soluble in water, methanol, and acetone.
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XLogP3: 0.9 (indicating moderate hydrophilicity)
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Hydrogen Bond Donor Count: 16
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Hydrogen Bond Acceptor Count: 26
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Topological Polar Surface Area: 455 Ų
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Heavy Atom Count: 67
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Complexity: 1960 (indicating a highly complex structure)
Biological and Functional Properties:
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Low Cytotoxicity: Exhibits potent bioactivity at low concentrations (e.g., 1 µM for osteoclast inhibition) with minimal cytotoxicity even at high concentrations (up to 50 µM).
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Broad-Spectrum Signaling Inhibition: Inhibits multiple key signaling pathways (Akt, Erk, JNK, p38 MAPKs, IκBα, NF-κB, NFATc1) in osteoclastogenesis.
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Microbiome Modulation: Alters gut microbiota composition, increasing beneficial bacteria like Ruminococcus and enhancing immunotherapy response.
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Metabolic Effects: Induces changes in microbial metabolites, such as increasing taurine-conjugated bile acids.
Safety and Handling
Toxicological Profile:
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Demonstrates low cytotoxicity in cellular models, maintaining cell viability even at high concentrations (50 µM).
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Specific safety data regarding human toxicity, carcinogenicity, or mutagenicity are not provided in the available documents.
Handling Considerations:
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No specific handling, storage, or personal protective equipment recommendations are provided in the available documents.
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Standard precautions for handling laboratory chemicals should be applied.