Fact-checked by Grok 2 weeks ago

Stilbenoid

Stilbenoids are a diverse class of naturally occurring phenolic compounds, with over 400 identified to date, characterized by a core 1,2-diphenylethylene backbone, consisting of two phenyl rings connected by an ethylene bridge, often with hydroxyl, methoxy, or other substituents, and they function primarily as phytoalexins produced by plants in response to environmental stresses such as fungal infections or UV radiation.^[1]^[2] These secondary metabolites belong to the broader family of phenylpropanoids and exist in monomeric, oligomeric, or prenylated forms, with the trans (E) isomer typically being more stable and biologically active than the cis (Z) form.^[1] Stilbenoids are biosynthesized via the phenylpropanoid pathway, where stilbene synthase catalyzes the condensation of one molecule of 4-coumaroyl-CoA and three molecules of malonyl-CoA to form the basic stilbene skeleton.^[2] The most prominent stilbenoid, resveratrol (trans-3,5,4'-trihydroxystilbene), is abundant in grapes (Vitis vinifera), red wine, berries, peanuts, and rhubarb, serving as a key dietary source and exhibiting potent antioxidant properties that contribute to its health benefits.^[1]^[2] Other notable examples include piceatannol, pterostilbene, and oligomeric forms like ε-viniferin, found in sources such as blueberries (Vaccinium species), Gnetum species, and the bark of Morus alba.^[1] Stilbenoids are distributed across various plant families, including Vitaceae, Moraceae, and Cyperaceae, with their production often upregulated under biotic or abiotic stress conditions.^[2] Stilbenoids demonstrate a wide range of biological activities, including antioxidant, anti-inflammatory, cardioprotective, neuroprotective, antidiabetic, and anticancer effects, primarily through mechanisms such as scavenging free radicals, modulating signaling pathways like NF-κB and AMPK, and inhibiting enzymes involved in inflammation or tumor progression.^[1]^[2] For instance, resveratrol has been shown to reduce oxidative stress, lower blood pressure, and prevent platelet aggregation, contributing to cardiovascular health, while piceatannol exhibits antimelanogenic and antiproliferative properties useful in skin depigmentation and cancer therapy.^[1] Their antimicrobial and antifungal roles in plants extend to potential therapeutic applications against bacterial pathogens and in cosmetics for photoprotection and anti-aging.^[3] Despite promising preclinical data, the low bioavailability of many stilbenoids, such as resveratrol, poses challenges for clinical translation, prompting research into derivatives and delivery systems to enhance efficacy. As of 2025, research continues to explore stilbenoid derivatives for enhanced therapeutic applications, including cancer metabolism inhibition and treatment of chronic obstructive pulmonary disease.^[2]^[4]^[5]

Chemical Characteristics

Structure and Nomenclature

Stilbenoids are a class of secondary metabolites characterized by a core C6–C2–C6 carbon skeleton derived from stilbene, consisting of two aromatic phenyl rings connected by a central ethylene bridge in the trans (E) configuration.^[1] This parent structure, known as stilbene or trans-1,2-diphenylethene, features the formula C6H5–CH=CH–C6H5, where the double bond imparts planarity and stability to the molecule. Stilbenoids are specifically defined as hydroxylated derivatives of this stilbene backbone, with one or more phenolic hydroxyl groups attached to the phenyl rings, distinguishing them within the broader phenylpropanoid family of plant-derived compounds.^[3] The ethylene bridge in stilbenoids is typically in the (E)-configuration, though (Z)-isomers can occur and are less stable.^[1] Key functional groups include the phenolic hydroxyls, which are primarily located on the aromatic rings and contribute to the compounds' polarity and reactivity; common positions for substitution are 3, 5 on one ring (ring A) and 4' on the other (ring B), following standard stilbene numbering where the ethylene carbons are designated as 1 (α) and 2 (β), with ring attachments at these points.^[1] Rings A and B are benzene rings, with positions numbered clockwise from the ethylene attachment; hydroxyl groups replace hydrogens at specified sites in stilbenoids. Nomenclature for stilbenoids follows International Union of Pure and Applied Chemistry (IUPAC) conventions for stilbene derivatives, systematically describing substitutions on the core structure.^[6] Monomeric stilbenoids are named as substituted stilbenes, often with the (E) prefix for the trans isomer and locants indicating hydroxyl or other group positions. For instance, resveratrol, a prototypical stilbenoid, is designated as (E)-3,5,4'-trihydroxystilbene in common usage, reflecting hydroxyl groups at positions 3 and 5 on ring A and 4' on ring B; its full IUPAC name is 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol.^[6] This positional classification extends to other variants, such as piceatannol ((E)-3,5,3',4'-tetrahydroxystilbene), enabling precise identification based on substitution patterns rather than exhaustive listing of all possible isomers.^[1]

Reactivity and Derivatives

Stilbenoids exhibit notable reactivity under ultraviolet (UV) irradiation, primarily through photocyclization reactions that convert the trans isomer to cis-stilbene, followed by intramolecular cyclization to form dihydrophenanthrenes. This process, known as the Mallory reaction, involves excitation of the stilbene chromophore at wavelengths around 300-350 nm, leading to a singlet excited state that facilitates 6π-electrocyclization to yield the strained trans-4a,4b-dihydrophenanthrene intermediate, which is often unstable and can revert or oxidize further under aerobic conditions.^[7] The reaction is reversible, with cis-trans isomerization occurring rapidly upon exposure to light, and it has been observed in various stilbenoid derivatives, such as resveratrol, where iodine or air serves as an oxidant to trap the dihydrophenanthrene as a phenanthrene.^[8] Oxidation of stilbenoids, particularly under enzymatic or chemical conditions, promotes polymerization through radical coupling mechanisms, resulting in oligostilbenoids such as dimers (e.g., ε-viniferin) and higher oligomers. This reactivity stems from the electron-rich stilbene core, which generates phenoxy radicals upon one-electron oxidation, enabling regioselective C-C or C-O bond formation at ortho positions relative to phenolic hydroxyl groups.^[9] Synthetic methods often employ oxidants like silver carbonate or horseradish peroxidase to mimic these couplings, yielding complex oligostilbenoids with defined stereochemistry.^[10] Common derivatives of stilbenoids include glycosides, such as resveratrol-3-O-β-glucoside (piceid) and glucuronides, which enhance water solubility and stability. These are synthesized enzymatically using glycosyltransferases or chemically via Koenigs-Knorr glycosylation, where the aglycone is reacted with protected sugar halides in the presence of silver oxide to form β-glycosidic bonds.^[11] Prenylated forms, like arachidin-1, incorporate isoprenoid units at the aromatic ring, typically via prenyltransferase enzymes in biosynthesis or synthetically through acid-catalyzed Friedel-Crafts alkylation of stilbene precursors with dimethylallyl bromide.^[12] These modifications alter lipophilicity and biological availability without disrupting the core stilbene framework. Stilbenoids display sensitivity to environmental factors, including light-induced isomerization and pH-dependent degradation, which can lead to cis-trans conversion or oxidation in neutral to alkaline conditions (pH >7) due to deprotonation of phenolic groups.^[13] To mitigate instability, storage under inert atmosphere and low temperatures is recommended, as exposure to UV or fluorescent light accelerates photocyclization, while acidic pH (below 5) generally preserves the trans form. Analytical detection relies on high-performance liquid chromatography (HPLC) coupled with UV or mass spectrometry for quantification and separation of isomers, often using reversed-phase C18 columns with methanol-water gradients.^[14] Nuclear magnetic resonance (NMR) spectroscopy, particularly 1H and 13C NMR, provides structural confirmation of derivatives and reaction products by identifying shifts in olefinic protons (δ 6.5-7.5 ppm) and coupling patterns indicative of cis or trans configurations.^[15]

Biosynthesis and Sources

Biosynthetic Pathway

Stilbenoids are synthesized in plants through the phenylpropanoid pathway, which begins with the amino acid L-phenylalanine. The first committed step is catalyzed by phenylalanine ammonia-lyase (PAL), which deaminates L-phenylalanine to trans-cinnamic acid, serving as the rate-limiting reaction in the pathway.^[16] Subsequent hydroxylation by cinnamate 4-hydroxylase (C4H), a cytochrome P450 monooxygenase, converts trans-cinnamic acid to p-coumaric acid.^[16] Finally, 4-coumarate:CoA ligase (4CL) activates p-coumaric acid to p-coumaroyl-CoA, the key intermediate that branches toward various phenylpropanoid derivatives, including stilbenoids.^[16] The pivotal enzyme in stilbenoid biosynthesis is stilbene synthase (STS), a type III polyketide synthase that condenses one molecule of p-coumaroyl-CoA with three molecules of malonyl-CoA to produce the monomeric stilbenoid resveratrol (trans-3,5,4'-trihydroxystilbene) after decarboxylation and cyclization.^[16] STS enzymes belong to multigene families, with plants like grapevine (Vitis vinifera) harboring dozens of STS genes that share high sequence similarity and exhibit tissue-specific expression. These genes encode proteins that compete with chalcone synthase for the same substrates, directing metabolic flux toward stilbenoids rather than flavonoids. Biosynthesis of stilbenoids is tightly regulated at the transcriptional level by transcription factors such as subgroup 2 R2R3-MYB proteins (e.g., MYB14 and MYB15 in grapevine), which bind promoter regions of STS genes as well as upstream phenylpropanoid genes like PAL, C4H, and 4CL to coordinate pathway activation. Environmental triggers, including ultraviolet (UV) radiation, fungal pathogens, and mechanical wounding, strongly upregulate STS expression and stilbenoid accumulation; for instance, UV-C irradiation can induce a 10-fold increase in trans-resveratrol levels in grapevine berries by enhancing STS transcription.^[17] Fungal elicitors like those from Botrytis cinerea similarly activate the pathway via jasmonate and salicylic acid signaling, promoting resveratrol as a phytoalexin.^[17] Oligomeric stilbenoids, such as dimers (e.g., ε-viniferin) and higher oligomers, arise from variations in the pathway through oxidative coupling of resveratrol monomers, primarily catalyzed by peroxidases or laccase-like stilbene oxidases that utilize hydrogen peroxide or molecular oxygen to form C–C or C–O–C linkages.^[18] These enzymes facilitate region- and stereoselective dimerization and polymerization, often in response to oxidative stress conditions.^[18] Recent genetic engineering efforts have enhanced stilbenoid production by introducing STS genes into heterologous systems. In tobacco (Nicotiana tabacum), transgenic lines expressing grapevine 4CL-STS fusion genes under the constitutive CaMV35S promoter accumulate resveratrol up to 21 mg/kg fresh weight, conferring resistance to fungal pathogens.^[19] Similarly, yeast (Saccharomyces cerevisiae) engineered with plant-derived 4CL and STS genes, supplemented with precursors like p-coumaric acid, achieves resveratrol yields exceeding 300 mg/L in optimized strains.^[20]

Natural Occurrence

Stilbenoids are widely distributed in the plant kingdom, primarily serving as phytoalexins that contribute to defense against biotic and abiotic stresses. The family Vitaceae, particularly Vitis vinifera (grapevines), is a major source, with resveratrol and its glycosides accumulating in grape skins, seeds, and canes.^[1] Other notable plant families include Pinaceae, where species like Picea jezoensis (Jezo spruce) and Pinus sylvestris (Scots pine) produce piceatannol and its derivatives in bark, needles, and roots.^[21] Stilbenoids are also found in non-woody plants such as Arachis hypogaea (peanuts), where prenylated forms like arachidin accumulate in roots and seeds under stress; various berries including Vaccinium species (blueberries); and Cannabis sativa leaves, which contain multiple stilbenoid variants alongside cannabinoids.^[22]^[23]^[24] Beyond plants, stilbenoids occur in microbial sources, notably the Gram-negative bacterium Photorhabdus luminescens, a symbiont of entomopathogenic nematodes, which biosynthesizes tapinarof (3,5-dihydroxy-4-isopropyl-trans-stilbene) as part of its secondary metabolism. This compound acts as an aryl hydrocarbon receptor agonist with anti-inflammatory properties.^[25] Ecologically, stilbenoids in these organisms enhance survival in hostile environments, such as soil pathogens for plants or insect hosts for bacteria. Concentrations of stilbenoids vary significantly due to environmental factors, including stress responses and geography. In grapes, UV exposure triggers a marked increase in resveratrol levels in skins, often rising several-fold post-irradiation to bolster UV protection.^[26] Similarly, infection or wounding induces phytoalexin production across sources.^[27] Geographical terroir influences accumulation, with higher stilbene levels in grapevines from cooler climates or stressed soils compared to optimal conditions.^[28] Extraction from natural sources typically targets agricultural byproducts to promote sustainability. Grape canes and pomace from winemaking are processed via hydroalcoholic maceration or ultrasound-assisted methods using ethanol-water mixtures to yield stilbenoid-rich extracts.^[29] Tree bark from Pinaceae species, such as Picea abies, undergoes organosolv extraction with ethanol-water solvents to isolate antioxidants like piceatannol glycosides.^[30] These approaches minimize environmental impact while recovering bioactive compounds at concentrations up to several percent dry weight.^[31]

Classification and Types

Monomeric Stilbenoids

Monomeric stilbenoids represent the simplest class of stilbenoids, consisting of non-oligomerized, hydroxylated derivatives of the core stilbene structure (1,2-diphenylethene). These compounds are characterized by a C6-C2-C6 carbon skeleton with two phenyl rings connected by a central ethylene bridge, often featuring hydroxyl groups that confer biological relevance. Prominent examples include resveratrol (3,5,4'-trihydroxystilbene), abundant in grapes and recognized for its role as an antioxidant; piceatannol (3,3',4',5-tetrahydroxystilbene), isolated from rhubarb and other plants; and pterostilbene (3,5-dimethoxy-4'-hydroxystilbene), a naturally occurring dimethyl ether derivative of resveratrol found in blueberries and grapes.^[2]^[1]^[32] Structural variations among monomeric stilbenoids primarily arise from stereoisomerism and substitution patterns. They occur as cis (Z) or trans (E) isomers at the central double bond, with the trans configuration being more thermodynamically stable and predominant in natural sources due to lower steric hindrance. Hydroxylation typically occurs on the aromatic rings, with common positions including 3 and 5 on the A ring and 4' on the B ring, as seen in resveratrol; additional hydroxylation at 3' yields piceatannol. These modifications influence solubility, stability, and potential bioactivity, though monomers can also appear as glycosylated derivatives like piceid (resveratrol-3-O-β-D-glucoside).^[1]^[14] Early discoveries of monomeric stilbenoids date back to the mid-20th century, with resveratrol first isolated in 1939 by Japanese chemist Michio Takaoka from the roots of Veratrum grandiflorum (white hellebore), where it was identified through crystallization and spectroscopic analysis. Subsequent isolations expanded knowledge of their distribution, including piceatannol from rhubarb in later studies, highlighting their widespread occurrence in angiosperms.^[33]^[32]

Oligomeric and Glycosylated Stilbenoids

Oligostilbenoids represent a diverse subclass of stilbenoids characterized by the polymerization of two or more monomeric units, primarily through regioselective oxidative coupling mechanisms that form carbon-carbon (C-C) or ether linkages between the C6–C2–C6 scaffolds. These compounds arise in response to environmental stresses in plants, leading to intricate structures that enhance their stability and functionality compared to simple monomers. Dimers such as ε-viniferin exemplify this class, resulting from the 8-10′ coupling of two resveratrol units, commonly isolated from grapevines (Vitis vinifera). Trimers like ampelopsin C, found in Ampelopsis species such as Ampelopsis brevipedunculata, involve additional coupling of a resveratrol monomer to a dimeric intermediate, showcasing the stepwise assembly typical of these oligomers.^[34]^[35]^[36] The structural complexity of oligostilbenoids increases with oligomer size, featuring fused ring systems and varied linkage patterns that can include diaryl ether bonds alongside C-C connections. While dimers and trimers predominate, higher oligomers—up to eight or more resveratrol units—have been documented in families like Dipterocarpaceae and Cyperaceae, contributing to their rarity and challenging isolation. These multi-unit structures, often bearing hydroxyl and methoxyl substitutions, underscore the biosynthetic versatility of stilbenoids in specialized plant tissues such as bark and roots. Representative examples include vaticanol A, a trimer with ether linkages from Shorea species, illustrating how oxidative processes yield polycyclic frameworks.^[37]^[38]^[39] Glycosylated stilbenoids consist of stilbene aglycones conjugated to sugar groups, typically β-D-glucopyranosides, which confer enhanced water solubility and facilitate transport within plant tissues. Piceid (resveratrol-3-O-β-D-glucoside) is a well-known glycoside abundant in the inner bark of Norway spruce (Picea abies), where it accumulates as a defense compound. Similarly, astringin (piceatannol-3-O-β-D-glucoside) occurs in spruce bark alongside piceid, with the glucoside moiety improving aqueous solubility over the parent stilbenes and aiding extraction in industrial processes. These modifications maintain the core stilbene reactivity while broadening environmental adaptability.^[40]^[41]^[42] Rare glycosylated variants continue to emerge from conifer sources, exemplified by resveratroloside isolated from Pinus cembra bark in a 2025 study, which features a unique glycosylation pattern enhancing its polar properties. Pinostilbenoside, another recent find from the same species, complements this diversity, highlighting the untapped potential of alpine conifer barks for novel stilbene glycosides. Such compounds, built from monomeric stilbenoids like resveratrol and piceatannol, underscore the role of glycosylation in stilbenoid evolution and distribution.^[43]^[44]

Prenylated Stilbenoids

Prenylated stilbenoids form another important class, characterized by the attachment of prenyl (isoprenoid) groups to the core stilbene skeleton, which enhances lipophilicity and biological activity. These modifications arise from the incorporation of dimethylallyl pyrophosphate in the biosynthetic pathway and are common in plants like those in the Moraceae and Guttiferae families. Notable examples include arachidin-1 and arachidin-3 from peanuts (Arachis hypogaea), and p Prenylated resveratrol derivatives such as chiricanine A from South American plants. Prenylated stilbenoids exhibit potent antimicrobial and anticancer properties, often more so than their non-prenylated counterparts.^[2]

Biological Properties

Antioxidant and Anti-inflammatory Activities

Stilbenoids exhibit potent antioxidant properties primarily through their polyphenolic structure, which enables electron donation from phenolic hydroxyl groups to neutralize reactive oxygen species (ROS). These compounds act via mechanisms such as hydrogen atom transfer (HAT), where the phenolic OH groups donate a hydrogen to form stable phenoxyl radicals, effectively scavenging free radicals like hydroxyl (HO·) and peroxyl (ROO·).^[45] Additionally, stilbenoids inhibit ROS production by activating the Nrf2 pathway, a key regulator of cellular antioxidant defenses, leading to upregulation of enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). For instance, resveratrol, a prototypical stilbenoid, demonstrates this in cellular models by enhancing Nrf2 nuclear translocation and reducing oxidative damage.^[46] In DPPH radical scavenging assays, resveratrol achieves an IC50 of 13.19 ± 4.78 μg/mL, underscoring its efficacy comparable to synthetic antioxidants.^[46] Structure-activity relationships among stilbenoids highlight that antioxidant potency correlates with the number and positioning of hydroxyl groups on the aromatic rings. Compounds with more hydroxyl substituents, such as piceatannol (four OH groups), exhibit superior radical scavenging compared to resveratrol (three OH groups), as the additional ortho-dihydroxyl facilitates semiquinone radical formation and electron delocalization.^[45] Theoretical density functional theory (DFT) evaluations confirm that HAT is the preferred mechanism for stilbenes with multiple phenolic OH, with bond dissociation enthalpies decreasing as hydroxyl count increases, thereby enhancing stability against various radicals.^[45] This SAR is evident in cellular assays where piceatannol outperforms resveratrol in quenching singlet oxygen and protecting against lipid peroxidation. The anti-inflammatory activities of stilbenoids stem from their ability to modulate key signaling pathways, including inhibition of nuclear factor kappa B (NF-κB) activation, which suppresses the transcription of pro-inflammatory genes. By blocking NF-κB translocation to the nucleus, stilbenoids reduce the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), thereby decreasing prostaglandin and nitric oxide production.^[47] They also attenuate cytokine release, such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β, IL-6), in lipopolysaccharide (LPS)-stimulated cell models; for example, resveratrol at micromolar concentrations inhibits TNF-α secretion in macrophages by over 50%.^[47] Piceatannol similarly targets NF-κB and cytokine pathways, while pterostilbene shows enhanced potency due to its methoxy substitution improving bioavailability.^[47] In vitro and animal studies further validate these effects, particularly resveratrol's protection against oxidative stress in cardiovascular contexts. In rat cardiomyocytes exposed to hydrogen peroxide, resveratrol (10-50 μM) restores Nrf2-mediated antioxidant enzyme levels and reduces ROS-induced apoptosis.^[46] Animal models demonstrate cardioprotection; in mice subjected to ischemia-reperfusion, oral resveratrol (30 mg/kg for 7 days) decreases myocardial infarct size from 33% to 20% by mitigating oxidative damage and inflammation via Nrf2 and NF-κB inhibition.^[46] In aging rat hearts, chronic administration (0.05 mg/mL in drinking water for 12 weeks) lowers ROS levels and preserves cardiac function, linking stilbenoid activity to reduced inflammatory cytokine profiles.^[46] These findings emphasize stilbenoids' role in cellular protection without direct antimicrobial involvement.

Antimicrobial and Phytoalexin Functions

Stilbenoids function as phytoalexins in plants, serving as inducible antimicrobial defenses synthesized in response to pathogen attack or stress. These secondary metabolites accumulate in infected tissues to inhibit the growth and spread of invading microbes, contributing to plant resistance mechanisms.^[48] For instance, in grapevines (Vitis vinifera), resveratrol is rapidly produced upon infection by the fungal pathogen Botrytis cinerea, the causative agent of gray mold, where it suppresses conidial germination by approximately 50% at concentrations of 90 μg/mL and reduces mycelial growth at 60–140 μg/mL.^[49] Similarly, in peanuts (Arachis hypogaea), stilbenoid phytoalexins such as arahypin derivatives accumulate in seeds challenged by Aspergillus flavus or Aspergillus caelatus, enhancing resistance to these aflatoxin-producing fungi by disrupting pathogen development. In pine trees (Pinus spp.), pinosylvin stilbenes are upregulated following infection by pine wood nematodes (Bursaphelenchus xylophilus), exhibiting nematicidal activity that limits nematode proliferation and supports host defense.^[50] The antimicrobial mechanisms of stilbenoids primarily involve disruption of microbial cell membranes and inhibition of essential enzymes, leading to leakage of intracellular contents and impaired metabolic functions. These compounds preferentially target Gram-positive bacteria compared to Gram-negative ones, as the latter possess an outer lipopolysaccharide membrane and efflux systems that reduce permeability and compound entry, resulting in increased membrane permeability and cell death in Gram-positives.^[51] For example, pterostilbene, a dimethylated resveratrol analog, demonstrates bacteriostatic effects against Staphylococcus aureus with minimum inhibitory concentrations (MICs) ranging from 16–64 μg/mL, primarily through membrane destabilization rather than bactericidal action at higher doses.^[51] Against fungi, stilbenoids like resveratrol interfere with spore germination and hyphal extension by altering membrane fluidity and inhibiting oxidative enzymes in pathogens such as B. cinerea.^[52] Beyond plant-based production, stilbenoids also occur in bacterial contexts, where they bolster symbiotic defenses against pathogens. Tapinarof, a stilbenoid derived from bacteria (Photorhabdus spp.) symbiotically associated with entomopathogenic nematodes (e.g., Heterorhabditis spp.), exhibits antibiotic properties that protect insect hosts from invading microbes, including Gram-positive bacteria, by modulating pathogen metabolism and enhancing overall symbiosis efficacy.^[53]

Applications and Recent Research

Health and Therapeutic Uses

Stilbenoids, particularly resveratrol, have garnered attention for their potential therapeutic roles in human health, primarily through modulation of cellular pathways that address age-related and chronic diseases. Resveratrol activates SIRT1, a key deacetylase enzyme, which enhances neuronal survival and reduces amyloid-beta toxicity in Alzheimer's disease models, thereby promoting neuroprotection. A 2025 review highlights that this activation mitigates oxidative stress and inflammation in the brain, though low oral bioavailability—due to rapid glucuronidation and sulfation, resulting in plasma concentrations of 0.3–2.4 μM—limits its efficacy, with therapeutic levels requiring >10 μM. Brain penetration is confirmed, as resveratrol and its metabolites are detectable in cerebrospinal fluid, leading to reduced Aβ accumulation and improved cognitive markers in preclinical studies.^[54] In oncology, stilbenoid derivatives exhibit promising anticancer properties by targeting hypoxia-inducible factor-1α (HIF-1α), a transcription factor overexpressed in solid tumors that drives metabolic adaptation under low oxygen. A 2024 study synthesized derivatives and identified compound 28e as highly potent, reducing HIF-1α protein levels and downstream genes like GLUT1 and PDK1 without altering mRNA expression, thereby inhibiting glycolysis, glucose uptake, and ATP production in hypoxic cancer cells. In xenograft mouse models, 10 mg/kg of 28e suppressed tumor growth by 40% and diminished HIF-1α in tumor tissues, suggesting potential as adjunctive therapy for hypoxic tumors.^[4] Cardiovascular and metabolic benefits of stilbenoids include anti-hyperglycemic effects, with resveratrol improving insulin sensitivity in human trials. In a randomized controlled trial involving obese men, 150 mg/day of resveratrol for 30 days enhanced skeletal muscle mitochondrial function, reduced fasting glucose and insulin levels, and increased the Matsuda index of insulin sensitivity, indicating better systemic metabolic control. These effects stem from resveratrol's ability to boost AMP-activated protein kinase activity, though results vary across studies due to dosage and population differences.^[55] For gut health, stilbenoids support microbiota composition and intestinal barrier integrity in animal models of damage. A 2025 review details how resveratrol at 100 mg/kg in diquat-challenged piglets upregulates tight junction proteins like occludin, claudin-1, and ZO-1, while enriching beneficial bacteria such as Bifidobacterium and reducing pro-inflammatory taxa like Akkermansia in dextran sulfate sodium-induced colitis mice. Pterostilbene, another stilbenoid, at 400 mg/kg in stressed broilers increases villus height and superoxide dismutase activity, alleviating permeability and oxidative damage to the mucosal barrier. These findings underscore stilbenoids' role in mitigating intestinal injury through microbiota modulation and anti-inflammatory actions.^[56] Recent clinical trials emphasize resveratrol's evaluation in neurodisorders, though bioavailability remains a hurdle. A phase II randomized, double-blind, placebo-controlled trial in 119 patients with mild-to-moderate Alzheimer's disease administered up to 2 g/day resveratrol for 52 weeks, demonstrating safety and tolerability with measurable brain penetration via CSF levels, but no cognitive improvement and accelerated brain volume loss. A 2025 review notes ongoing efforts to address low bioavailability through formulations like nanocapsules, with phase II data informing larger trials for neurodegenerative conditions, where resveratrol alters biomarkers like Aβ40 without clear therapeutic gains yet.^[57]^[58]

Industrial and Agricultural Potential

Stilbenoids, particularly resveratrol, have gained attention in the food industry for their role as natural preservatives in wine production and dietary supplements due to their antimicrobial and antioxidant properties. In winemaking, resveratrol concentrations in red wines range from 0.1 to 10.7 mg/L, contributing to shelf-life extension by inhibiting microbial growth, while extracts from grape sources are incorporated into supplements to enhance product stability and health claims. Enrichment techniques, such as UV-C irradiation applied preharvest or postharvest to grapes, significantly boost stilbenoid levels; for instance, daily UV-C exposure maintains high resveratrol content in grape berries, improving wine quality without synthetic additives.^[59]^[60] In pharmaceutical production, biotechnological approaches using engineered microorganisms offer sustainable synthesis of stilbenoids like resveratrol as precursors for drug development. A modular coculture system in Escherichia coli divides the biosynthetic pathway, with one strain producing *p*-coumaric acid from glucose and another converting it to resveratrol via 4-coumarate:CoA ligase (4CL) and stilbene synthase (STS) enzymes, enhanced by CRISPR interference to increase malonyl-CoA availability. This method achieved a yield of 204.8 mg/L resveratrol from a glucose-arabinose mixture, demonstrating scalability for industrial precursor production while minimizing reliance on plant extraction.^[61] Agricultural applications leverage stilbenoids, especially viniferins, as natural fungicides to combat grape pathogens and reduce chemical pesticide use. Extracts rich in δ-viniferin and pterostilbene from grapevine canes exhibit toxicity to Plasmopara viticola zoospores, the causal agent of downy mildew, by impairing their mobility and inhibiting disease progression in vineyards. These phytoalexins enable eco-friendly crop protection, potentially decreasing fungicide applications by supporting integrated pest management in viticulture.^[62] Emerging uses in 2025 highlight stilbenoids' incorporation into animal feed for livestock growth promotion and stress mitigation. Resveratrol supplementation at 90 mg/kg in piglets under oxidative stress enhances beneficial gut microbiota and metabolites like indole-3-carbinol, improving overall performance. In broilers, 500 mg/kg resveratrol during cold exposure boosts antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), reducing markers of stress like malondialdehyde (MDA), while 400 mg/kg pterostilbene alleviates diquat-induced oxidative damage and supports gut barrier integrity. These findings from recent livestock trials underscore stilbenoids' potential to enhance feed efficiency and animal welfare.^[56] Sustainability efforts focus on valorizing winery waste, such as grape pomace, through efficient stilbenoid extraction to support circular economy practices. Pomace from varieties like Cabernet yields up to 102.1 mg/kg dry weight of resveratrol via methanol-based extraction followed by reverse-phase high-performance liquid chromatography (RP-HPLC) analysis, transforming 25–30% of winemaking byproducts into valuable compounds for food and pharma industries. This approach minimizes environmental waste while providing a renewable source of bioactive stilbenoids, aligning with green processing goals.^[63]^[59]

References

[1]
Biological Activities of Stilbenoids - PMC - PubMed Central
Stilbenoids are a group of naturally occurring phenolic compounds found in various plant species. They share a common backbone structure known as stilbene, ...
[2]
Resveratrol and Other Natural Oligomeric Stilbenoid Compounds ...
Aug 14, 2023 · Natural stilbenes were shown to possess a wide range of biological activities, such as antioxidant, anti-inflammatory, antihyperglycemic, cardioprotective, ...
[3]
Stilbenoids: A Natural Arsenal against Bacterial Pathogens - PMC
From a chemical point of view, stilbenoids share the stilbene backbone, consisting of two differently substituted aromatic rings, which is linked by an ethylene ...
[4]
Resveratrol | C14H12O3 | CID 445154 - PubChem - NIH
Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of ...Cis-Resveratrol · Resveratrol 3-O-glucuronide · trans-Resveratrol 4'-sulfate
[5]
Photochemical Oxidative Cyclisation of Stilbenes and Stilbenoids ...
Oxidative Photocyclization. The reaction pathway of what should be ... The photochemistry of stilbenoid compounds and their role in materials technology.
[6]
[PDF] Photocyclization of stilbenes and stilbenoids - Research Trends
The intermediate dihydrophenanthrene. 3 or 4 is unstable and can be trapped by oxidation to form a phenanthrene 5, or by elimination given a suitable ...Missing: UV | Show results with:UV
[7]
Update on Phytochemistry and Pharmacology of Naturally Occurring ...
Nov 24, 2017 · Resveratrol oligomers (REVs), a major class of stilbenoids, are biosynthesized by regioselective oxidative coupling of two to eight units of ...
[8]
Strategies and Methods for the Syntheses of Natural Oligomeric ...
Aug 6, 2025 · Most of the work is based on the dimerisation of stilbenoid monomers with help of one-oxidant reagents or through acid catalysis. Mechanistic ...
[9]
(PDF) Recent biotechnological progress in enzymatic synthesis of ...
... Enzymatic synthesis of flavonoid-and stilbenoid glycosides …
[10]
Synthesis of C-prenylated analogues of stilbenoid methyl ethers and ...
An efficient and versatile synthesis of the naturally occurring C-prenylated stilbenoid methyl ethers and their synthetic analogues is presented.
[11]
Stability and Photoisomerization of Stilbenes Isolated from the Bark ...
Feb 16, 2021 · Stilbenes are photosensitive and UV and fluorescent light induce trans to cis isomerisation via intramolecular cyclization.
[12]
Current research on determination of medically valued stilbenes and ...
Depending on the water purification method the pH of clean laboratory water, with a pH range of 5–9, can affect the ionization of stilbenoids (pKa ∼9.99 in ...
[13]
HPLC Analysis and NMR Identification of Homoisoflavonoids and ...
Twelve of the 19 were identified by comparison of Rt values with those of authentic homoisoflavonoids and stilbenoids, co-elution and by preparative isolation ...
[14]
https://www.sciencedirect.com/science/article/pii/S2772391724000562
[15]
https://journals.sagepub.com/doi/pdf/10.1177/1934578X0900401011
[16]
https://doi.org/10.3389/fpls.2025.1571825
[17]
Stilbene biosynthesis in the needles of spruce Picea jezoensis
Resveratrol and piceatannol derivatives have been detected in the spruce bark, needles, and roots. We analyzed seasonal variation in stilbene spectrum and ...
[18]
Antioxidant Assessment of Prenylated Stilbenoid-Rich Extracts ... - NIH
Nov 10, 2021 · The stilbenoid-rich extracts from peanut hairy roots show high antioxidant capacity and merit further study as potential nutraceuticals to promote human health.
[19]
The stilbene profile in edible berries | Phytochemistry Reviews
Jun 15, 2018 · Postharvest treatment of grape varieties with UV-C resulted in higher concentrations of stilbenes, such as E-resveratrol, piceatannol, ...The Stilbene Profile In... · Abiotic Preharvest... · Abiotic Postharvest...<|separator|>
[20]
Stilbenoids and cannabinoids from the leaves of Cannabis sativa f ...
Dec 13, 2018 · Three new stilbenoids (1-3) and 16 known stilbenoids (4-6) and cannabinoids (7-19) were isolated from the leaves of hemp (Cannabis sativa L.).
[21]
Tapinarof - Wikipedia
Tapinarof, also known as benvitimod, is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes. It is a product of ...Missing: microbial | Show results with:microbial
[22]
Impact of Environmental Factors on Stilbene Biosynthesis - PMC
Oxidative stress may also be induced by many abiotic conditions, such as drought, thermal stress, ultraviolet radiation, mechanical stress, heavy metals, salts, ...Missing: geographical | Show results with:geographical
[23]
Stilbenoids: Chemistry, occurrence, bioavailability and health effects ...
Mar 31, 2021 · Stilbenoids are synthesized by plants in response to external stimuli such as infection and UV-irradiation, thus known as phytoalexins.
[24]
Terroir and variety: Two key factors for obtaining stilbene-enriched ...
The aim of this study was to determine the contribution of both variety and terroir on stilbene concentration and on stilbene induction capacity after UVC light ...Missing: variations exposure
[25]
Characterization of Some Stilbenoids Extracted from Two Cultivars ...
The extraction of stilbenoids from grapevine pruning canes has been proposed as a cost-effective method for obtaining high-value phytochemicals [11,19,20,21].
[26]
Environmentally Friendly Extraction from Picea Abies Bark as an ...
Jul 3, 2023 · We investigated organosolv extraction of antioxidants from Picea abies bark using various ratios of ethanol/water with the goal of obtaining ...
[27]
Various Extraction Methods for Obtaining Stilbenes from Grape ... - NIH
The presented work compares several extraction methods: maceration at laboratory temperature, extraction at elevated temperature, fluidized-bed extraction, ...
[28]
Piceatannol Increases Antioxidant Defense and Reduces Cell Death ...
Piceatannol is a naturally phenolic compound found in a variety of plant sources including grapes, rhubarb, peanuts, sugarcane, white tea, and the seeds of ...Piceatannol Increases... · 2. Materials And Methods · 3. Results And Discussion<|control11|><|separator|>
[29]
Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy?
Jul 11, 2016 · The average red wine can be expected to contain ∼1.9 ± 1.7 mg trans-resveratrol/L. Sources and Recommended Daily Intake of Resveratrol. It is ...
[30]
Resveratrol: Twenty Years of Growth, Development and Controversy
Resveratrol was first isolated in 1939 by Takaoka from Veratrum grandiflorum O. Loes. Following this discovery, sporadic descriptive reports appeared in the ...
[31]
Resveratrol oligomer structure in Dipterocarpaceaeous plants - PMC
Apr 30, 2020 · Oligostilbenoids are a group of natural products derived from the oxidative coupling of C6–C2–C6 units found in some plant families.Missing: CC | Show results with:CC
[32]
Chiral analysis of E‐ε‐viniferin enantiomers, towards a new ...
Jan 13, 2023 · E-ε-viniferin is a stilbene dimer ... Within the common stilbenes resveratrol is the basic monomeric unit, which can lead to oxidative coupling ...
[33]
[PDF] Simultaneous determination of resveratrol derivatives in Vitis ...
The present study used five compounds, including four isolated ones, ampelopsin C,. (+)-vitisin A, (-)-vitisin B, and (+)-e-viniferin, and one purchased ...
[34]
Chemistry and Biology of Resveratrol-Derived Natural Products
Apr 2, 2015 · Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum ...
[35]
Resveratrol Oligomers for the Prevention and Treatment of Cancers
Resveratrol oligomers are characterized by the polymerization of two to eight resveratrol units and even more and are the largest group of oligomeric stilbenes ...Missing: oligostilbenoid | Show results with:oligostilbenoid
[36]
Chemistry and Pharmacology of Cyperaceae Stilbenoids: A Review
May 10, 2021 · Stilbenes possess a wide range of multi-faceted biological activities, among them antitumor, antioxidant, antiplatelet, antimicrobial, ...6.1. Promising Effects... · 6.1. 1. Antitumor Activity · 6.1. 2. Antioxidant Activity
[37]
Stilbenoids of Norway spruce bark: does the variability caused by ...
Apr 13, 2022 · In plants, stilbenoids serve as defensive compounds against a wide variety of environmental stressors, including protection from ultraviolet (UV) ...Missing: exposure | Show results with:exposure
[38]
Stability and Photoisomerization of Stilbenes Isolated from the Bark ...
Stilbene glucosides (trans-astringin, trans-isorhapontin and trans-piceid) in the solid crude extract showed 100% recovery when assessed for their stability ...
[39]
Glycosylation of Stilbene Compounds by Cultured Plant Cells - PMC
Mar 22, 2020 · These studies indicate that the glycosylation of bioactive compounds can enhance their water-solubility and intestinal absorption. The ...Missing: astringin | Show results with:astringin
[40]
Stilbene Glycosides in Pinus cembra L. Bark
The present study reports the isolation of two stilbene glycosides, resveratroloside and pinostilbenoside, from Pinus cembra L. bark. Their ...
[41]
Stilbene Glycosides in Pinus cembra L. Bark - MDPI
The present study reports the isolation of two stilbene glycosides, resveratroloside and pinostilbenoside, from Pinus cembra L. bark.
[42]
https://pmc.ncbi.nlm.nih.gov/articles/PMC7145310/
[43]
https://pubmed.ncbi.nlm.nih.gov/40431024/
[44]
https://www.mdpi.com/2223-7747/14/10/1459
[45]
Biological Activity of Peanut (Arachis hypogaea) Phytoalexins and ...
When infected by a microbial pathogen, the peanut plant (Arachis hypogaea) becomes a potent producer of a distinctive set of stilbene-derived phytoalexins, (3–5) ...
[46]
Biological Activity of Resveratrol, a Stilbenic Compound from ...
Resveratrol was shown to significantly reduce mycelial growth of B. cinerea at concentrations ranging from 60 to 140 μg/ml.Missing: stilbenoids | Show results with:stilbenoids
[47]
Enhanced accumulation of pinosylvin stilbenes and related gene ...
Apr 22, 2021 · Our results suggest that pinosylvin-type stilbenoid biosynthesis is highly responsive to PWN infection and plays an important role in PWN resistance of P. ...
[48]
Antimicrobial activity of resveratrol-derived monomers and dimers ...
Dec 20, 2019 · Stilbenoids are an intriguing structural class of natural polyphenols characterized by a diverse array of biological and potential therapeutic ...
[49]
Inhibitory activity of stilbenes against filamentous fungi - PMC - NIH
Resveratrol exhibited inhibitory activity against yeasts and filamentous fungi (Seppanen et al., 2019) such as Botrytis cinerea (Adrian et al., 1997; Hoss et al ...
[50]
tapinarof | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY
It is a naturally occurring polyphenol derived from bacteria that exist symbiotically with entomopathogenic nematodes. AhR was identified as the primary ...
[51]
Resveratrol as a Therapeutic Agent in Alzheimer's Disease - MDPI
Resveratrol activates SIRT-1, which promotes a Th2 immune response and exerts anti-inflammatory effects, while inhibiting the STAT-1/STAT-2 and NF-κB/MAPK ...
[52]
Stilbenoid derivatives as potent inhibitors of HIF-1α-centric cancer ...
In this study, stilbenoid derivatives were designed, synthesized, and assessed for their capacity to inhibit HIF-1α-associated cancer metabolism.<|control11|><|separator|>
[53]
The therapeutic potential of resveratrol: a review of clinical trials
Sep 25, 2017 · Timmers et al. found that treatment of obese men with 150 mg/day of resveratrol for 30 days resulted in improved cellular and systemic markers ...
[54]
Unlocking Gut Health: The Potent Role of Stilbenoids in Intestinal ...
Stilbenoids contribute to gut health by enhancing intestinal morphology, supporting mucosal immune responses, regulating gut microbiota composition, modulating ...
[55]
A randomized, double-blind, placebo-controlled trial of resveratrol ...
Conclusions: Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood–brain barrier to have CNS effects. Further ...
[56]
Resveratrol: Molecular Mechanisms, Health Benefits, and Potential ...
Jun 11, 2025 · Given the low bioavailability of RES and the potential for adverse reactions in clinical applications, we summarize and discuss its safety ...
[57]
Resveratrol-based biorefinery models for favoring its inclusion along ...
Jan 15, 2024 · Resveratrol can be found in a hydroxylated form (as dihydroxy stilbene) containing higher stilbene proportion and lower amount of hydroxyl ...Review · 2. Resveratrol: Properties... · 5. Resveratrol Production
[58]
Chemistry, Biosynthesis and Pharmacology of Viniferin: Potential ...
The dimerization typically occurs (Scheme 2) through two region-isomeric modes: the 8–10′ coupling (as found in ε-viniferin) and the 3–8′ coupling (δ-viniferin) ...<|separator|>
[59]
Modular engineering of E. coli coculture for efficient production of ...
Mar 15, 2022 · Microbial production of resveratrol suffers from metabolic burden and low malonyl-CoA availability, which is a big challenge for synthetic ...
[60]
Review of the Pathogenic Mechanism of Grape Downy Mildew ...
Two stilbenoid compounds, δ-viniferin and pterostilbene, are toxic to the pathogen's zoospores, affecting their mobility and thus inhibiting disease ...
[61]
Nutritional and Antioxidant Valorization of Grape Pomace from ...
Jul 5, 2025 · Its use not only contributes to waste reduction but also represents a potential source of extraordinary income. Grape pomace contains minerals ...