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Flavanone

Flavanones are a subclass of , which are naturally occurring polyphenolic compounds characterized by a 15-carbon consisting of two phenyl rings (A and B) connected by a heterocyclic ring (C). Unlike other such as flavones, flavanones feature a saturated C-ring with no between C2 and C3, and they possess a group at the C4 position, giving them the core structure of 2-phenylchroman-4-one or flavan-4-one. Common examples include , , and eriodictyol, often occurring as glycosides like and in plants. Flavanones are primarily found in citrus fruits such as oranges, lemons, grapefruits, and mandarins, where they contribute to the characteristic bitterness and serve as defense compounds against environmental stresses. They are also present in other plants like tomatoes, herbs, and , with concentrations varying widely; for instance, can contain 81–200 mg/L of soluble flavanones. Biosynthetically, flavanones are produced via the phenylpropanoid pathway, where isomerase converts naringenin-chalcone into the flavanone scaffold. These compounds exhibit diverse biological activities, including potent effects through scavenging and metal , as well as properties by inhibiting enzymes like 5-lipoxygenase. Flavanones demonstrate antibacterial activity against pathogens such as methicillin-resistant Staphylococcus aureus and anticancer potential, with showing inhibition of colon and growth in preclinical models. Their low water solubility limits , but enhances stability and solubility for potential applications in , , and pharmaceuticals.

Chemical Structure and Properties

Core Structure

Flavanones constitute a subclass of defined by the core backbone of 2,3-dihydro-2-phenylchromen-4-one, also known as 2-phenylchroman-4-one. This structure features a 15-carbon C6-C3-C6 skeleton, comprising two aromatic phenyl rings (designated A and B) linked by a central three-carbon chain that cyclizes to form a heterocyclic C ring. In flavanones, the central C3 unit manifests as a non-aromatic dihydropyrone ring fused to the A ring (a benzopyran moiety), with the B ring attached at position 2 and a at position 4; saturation occurs specifically at the 2,3 bond, distinguishing this ring from the aromatic pyrone in related . The saturation at positions 2 and 3 introduces a chiral center at carbon 2, resulting in two enantiomers: (2R)- and (2S)-flavanones. Naturally occurring flavanones predominantly exhibit the (2S) at C2, a stereochemical feature arising from their biosynthetic origins. Many flavanones exist in glycosylated forms, commonly as 7-O-glycosides where a moiety, such as rutinose or glucose, attaches to the hydroxyl group at position 7 on the A ring. Structurally, flavanones differ from flavones by the absence of a between and , which renders the C ring saturated and non-planar rather than the unsaturated, aromatic form in flavones. In comparison to , flavanones maintain the B ring attachment at of the C ring, whereas isoflavones feature this attachment at , altering the overall symmetry and substitution pattern.

Physical Properties

Flavanones are typically white to pale yellow crystalline solids at room temperature. These compounds exhibit poor solubility in water, with naringenin displaying a solubility of approximately 0.032 mg/mL, though values can vary slightly based on experimental conditions. In contrast, flavanones show high solubility in organic solvents such as ethanol (up to 50 mg/mL for naringenin) and DMSO. Solubility is influenced by factors including pH, where it increases under alkaline conditions due to deprotonation of phenolic groups, and glycosylation, which improves aqueous solubility compared to aglycone forms. Melting points of common flavanones generally fall within 200-250°C; for instance, hesperetin has a melting point of 227.5°C, while naringenin melts at 251°C. Boiling points are notably high, often exceeding 500°C under predicted conditions, reflecting their stability in the . Flavanones demonstrate sensitivity to light, heat, and oxidation, which can induce degradation or lead to through oxidative . Glycosylated flavanones, such as , exhibit greater resistance to these stressors than their aglycone counterparts.

Chemical Reactivity

Flavanones feature a 2-phenylchroman-4-one , characterized by a at the C4 position, which serves as a primary electrophilic site due to its conjugation with the A- and B-rings, facilitating nucleophilic additions and enolization. The alpha-methylene group at C3 provides enolizable hydrogens, enabling base-catalyzed formation and subsequent reactions such as aldol condensations or dehydrogenations. hydroxyl groups, commonly substituted at C5, C7 on the A-ring, and C4' on the B-ring (as in naringenin), act as nucleophilic sites prone to proton donation, hydrogen bonding, and , influencing overall reactivity in acidic or oxidative environments. A key transformation involves to flavones through dehydrogenation at the C2-C3 bond, often mediated by oxidants such as iodine or (III) acetate, which abstract the alpha-hydrogens at C3 and eliminate to form the α,β-unsaturated system. reactions preferentially target the C7 phenolic hydroxyl, where the deprotonated phenoxide acts as a toward activated sugars, enhancing polarity and stability, as demonstrated in synthetic protocols yielding 7-O-glycosylflavanones. Oxidation of ortho-dihydroxylated B-rings can proceed to semiquinone radicals and then to quinones via two-electron transfer, particularly under enzymatic or chemical peroxidative conditions, altering the aromatic character and enabling further additions. The acid-base properties of flavanones are dominated by their hydroxyls, with values typically ranging from 7 to 10; for instance, naringenin exhibits values of 7.05 (C7-OH) and 8.84 (C5-OH), allowing in mildly basic or biological media to form phenoxides that enhance and reactivity toward electrophiles. In UV-Vis , flavanones display characteristic absorptions at 280-320 nm, primarily from the B-ring π-π* transitions (Band II ~270-290 nm) with a weaker shoulder for (~320 nm) due to limited conjugation across the saturated C-ring. NMR reveals diagnostic proton shifts, such as the methine H-2 at δ 5.3-5.5 ppm (doublet of doublets, J ≈ 3, 13 Hz), the diastereotopic H-3 protons at δ 2.7-3.1 ppm (two multiplets), and aromatic H-6/H-8 at δ 5.9-6.2 ppm (singlet or doublet), confirming the flavanone scaffold and substitution patterns.

Natural Occurrence and Sources

Plant Sources

Flavanones, a subclass of , are primarily distributed among the , , and plant families, where they occur as natural secondary metabolites. In the family, particularly species, flavanones such as and are abundant; for instance, (sweet orange) is a major source of , primarily extracted from its peel. Similarly, Citrus paradisi (grapefruit) contains high levels of in its fruits and peel. Within the family, flavanones have been identified in species like , isolated from root extracts. In the family, flavanone glycosides are present in plants such as Bidens gardneri. Flavanones accumulate in various tissues, including fruits, flowers, and leaves, often in glycosylated forms that enhance their and within cellular compartments like vacuoles. This localization supports their ecological roles, such as protecting tissues from (UV) radiation by absorbing harmful wavelengths and scavenging generated by UV exposure. Additionally, flavanones contribute to defense against pathogens, acting as agents and phytoanticipins that inhibit microbial growth and limit infection establishment. From an evolutionary perspective, flavanones represent critical intermediates in the flavonoid biosynthetic pathway, formed via isomerization and serving as precursors for downstream like flavones and . Genetic evidence from sequenced plant genomes, including those of early land plants and bryophytes, indicates that flavanone synthase genes emerged during the colonization of terrestrial environments around 550–470 million years ago, facilitating adaptations to UV stress and .

Dietary and Food Sources

Flavanones are predominantly found in fruits, which serve as the major dietary contributors to human intake. , for instance, contain at levels ranging from 20 to 70 mg per 100 g of fresh edible fruit, with variations depending on the variety such as or oranges. Grapefruit is a rich source of , approximately 20-30 mg per 100 g in the edible pulp, though concentrations can fluctuate with ripeness—peaking during early maturity—and , such as varieties exhibiting higher levels than white types. Other like lemons and limes contribute eriocitrin and smaller amounts of , typically 15-30 mg per 100 g combined flavanones in fresh edible portions. Herbs such as provide eriodictyol, a flavanone aglycone, at 12-54 mg per 100 g fresh weight, making them secondary but notable sources in herbal teas and seasonings. Food processing significantly influences flavanone availability. Juicing processes, particularly mechanical extraction, can result in losses of up to 30% of total flavanones due to incomplete transfer from the albedo and pulp to the liquid, with greater retention observed in low-speed pressing methods compared to industrial centrifugation. Heat treatments like pasteurization cause minor degradation, often less than 10-20% for glycosylated forms like hesperidin, as these compounds exhibit relative thermal stability up to 100°C, though prolonged exposure beyond 30 minutes may isomerize them into less bioactive chalcones. Conversely, fermentation enhances flavanone content; for example, lactic acid fermentation of orange juice increases extractable hesperidin and naringin by 20-50% through microbial breakdown of cell walls, improving bioavailability without significant loss of the core structure. Estimated daily flavanone intake varies by dietary patterns and region. In typical diets, consumption averages 20-50 mg per day, largely from sporadic intake of juices and fruits, contributing about 6-12% of total exposure based on national surveys like NHANES. Mediterranean diets yield higher intakes, approximately 27 mg per day or more, attributed to regular consumption of fresh and infusions, which elevates overall levels compared to patterns. These estimates underscore the nutritional relevance of flavanones, with intake influenced by seasonal availability and processing habits.

Biosynthesis in Plants

Enzymatic Pathways

The biosynthesis of flavanones in plant cells proceeds via the flavonoid branch of the phenylpropanoid pathway, where key enzymatic steps convert primary metabolites into the core flavanone structure. The pathway initiates with chalcone synthase (CHS), a type III polyketide synthase that catalyzes the stepwise condensation of one molecule of p-coumaroyl-CoA (derived from ) with three molecules of to yield naringenin chalcone, the open-chain precursor to flavanones. This reaction represents the first committed step in flavonoid production and occurs without additional cofactors beyond the substrates. Following formation, performs a stereospecific intramolecular cyclization, converting the chalcone into (2S)-naringenin, the foundational flavanone skeleton with its characteristic 2-phenylchroman structure. This ensures the correct (S)-configuration at the C-2 position, which is essential for subsequent diversification, and operates efficiently on the bicyclic chalcone substrate without requiring external cofactors. The sequential enzymatic pathway can be outlined as follows:
  1. p-Coumaroyl-CoA + 3 → Naringenin Chalcone (catalyzed by ).
  2. Naringenin Chalcone → (2S)-Naringenin (catalyzed by ).
In certain plant species, particularly early-studied cases like , an initially termed flavanone (FNS) was identified for direct flavanone formation; however, purification revealed it to function analogously to CHS by producing chalcone, which then requires CHI for cyclization. Modern understanding emphasizes CHS and CHI as the core sequential enzymes, with FNS variants more commonly associated with downstream production from flavanones. These reactions exhibit dependency on NADPH in associated upstream steps of the phenylpropanoid pathway (e.g., for cinnamate 4-hydroxylase) and are localized to the cytoplasmic face of the , where the enzymes may form multi-enzyme complexes to channel intermediates efficiently and minimize diffusion losses.

Regulation and Variations

The production of flavanones in plants is primarily regulated at the transcriptional level by the -bHLH-WDR (MBW) complex, where R2R3- and MYC-like bHLH transcription factors bind to promoter regions of early biosynthetic genes such as chalcone synthase (CHS) and chalcone isomerase (), activating their expression to initiate flavanone formation from precursors. These factors form heterotrimeric complexes that provide spatial and temporal specificity, ensuring flavanone synthesis occurs in response to developmental cues or stress signals in tissues like roots and leaves. For instance, in model systems, factors like AtMYB12 directly target CHS and promoters, enhancing the through the phenylpropanoid pathway toward flavanones. Environmental factors significantly modulate flavanone production through signaling cascades that converge on the MBW complex. UV light, particularly UV-B radiation, triggers photoreceptor-mediated activation of transcription factors such as MYB12 and MYB75, upregulating and expression to boost flavanone accumulation as a protective response against oxidative damage. Wounding induces and signaling, which in turn activate bHLH factors to enhance early genes, leading to localized flavanone increases for defense against pathogens. Nutrient stresses, including nitrogen or phosphorus limitation, stimulate (ABA)-dependent pathways that recruit and bHLH regulators, resulting in elevated flavanone levels to improve stress tolerance via mechanisms. Variations in flavanone accumulation across plant species arise from evolutionary differences in gene duplication and pathway specialization. In Citrus species, the presence of multiple chalcone-flavanone isomerase (CHI) genes, with up to 30 identified across species, contributes to higher overall flavonoid flux and substantial flavanone glycoside buildup like naringin in fruits due to enhanced cyclization efficiency. In contrast, some monocots, such as certain grasses, exhibit reduced or absent flavanone-derived branches owing to specialized variants or regulation of CHS and CHI that favor other flavonoid classes. Genetic engineering has demonstrated the potential to enhance flavanone yields by targeting these regulators in model plants. Overexpression of the R2R3-MYB transcription factor AtMYB111 in Arabidopsis activates CHS and CHI, increasing early flavonoid intermediates including flavanones, as evidenced by elevated pathway flux in transgenic lines. Similarly, ectopic expression of LjaMYB12 from Lonicera japonica in Arabidopsis boosts CHS/CHI transcription, resulting in higher flavanone accumulation alongside downstream products, highlighting the conserved role of MYB factors in yield enhancement. These studies underscore the efficacy of MBW-targeted engineering for optimizing flavanone production without disrupting plant growth.

Metabolism and Bioavailability

Human Absorption and Distribution

Flavanones, such as naringenin and hesperetin, are primarily absorbed in the human , with the serving as the main site of uptake through passive mechanisms. is generally less efficient for rutinoside glycosylated forms like hesperidin and naringin compared to their aglycone counterparts (naringenin and ), as they require prior in the to facilitate uptake of the aglycone via passive , despite improved solubility of glycosides. The of flavanone aglycones remains low, with human studies reporting cumulative urinary recovery of only 3-8% of the ingested dose, reflecting extensive first-pass metabolism and limited systemic exposure. For example, after of 130-135 mg doses, detection of conjugated metabolites occurs rapidly, within 20 minutes, indicating swift initial despite overall poor efficiency. In the bloodstream, absorbed flavanones undergo rapid phase II conjugation in the liver and intestines, circulating predominantly as and metabolites bound to proteins. These compounds exhibit strong affinity for (HSA), the primary transport protein in , with binding constants in the range of 10^4 to 10^5 M^{-1} for flavanones like naringenin and , which helps stabilize them during circulation but may limit free fractions available for tissue entry. Peak concentrations (C_{max}) are typically achieved 1-4 hours post-ingestion, varying by compound and source; for instance, reaches approximately 0.8-2 μM and naringenin 1-5 μM following juice consumption, with levels reflecting short-term dietary intake due to quick clearance. Tissue distribution of flavanones in humans may involve passive and other transporters, though are limited. Flavanones can inhibit OATP transporters like OATP1B1 and OATP1B3, potentially affecting co-transported compounds. Conjugated metabolites accumulate notably in the liver and , organs central to and elimination, with evidence of distribution to the via crossing the blood-brain barrier, potentially supporting neuroprotective effects. on precise tissue concentrations are limited, but animal models corroborate preferential localization in liver, , and neural . Excretion of flavanones occurs mainly through the kidneys, with over 90% of absorbed metabolites recovered in as conjugated forms and minor degradation products within 24 hours of ingestion. Biliary and fecal routes contribute minimally for parent compounds but may handle unabsorbed glycosides. The elimination is short, ranging from 1.3 to 3.1 hours for key flavanones like naringenin and , underscoring their transient presence in circulation and the need for repeated dietary exposure to maintain levels.

Biotransformation Processes

Flavanones, upon absorption in humans, primarily undergo biotransformation through phase I and phase II metabolic reactions in the intestine and liver, enhancing their solubility and facilitating excretion. Phase I metabolism involves cytochrome P450 (CYP450) enzymes that introduce hydroxyl groups via oxidation, often targeting the aromatic rings. For instance, naringenin, a representative flavanone, is hydroxylated at the 3'-position of the B-ring by human CYP1 family enzymes, such as CYP1B1, to form eriodictyol; this process occurs more efficiently with CYP1 enzymes compared to CYP2A enzymes. These oxidations prepare flavanones for subsequent conjugations but represent a minor pathway relative to direct phase II modifications in human liver microsomes. Phase II metabolism dominates flavanone biotransformation, involving conjugation to increase polarity. , catalyzed by UDP-glucuronosyltransferases (UGTs), occurs predominantly at phenolic hydroxyl sites, such as the 7-position in naringenin, forming conjugates like naringenin-7-O-glucuronide; this reaction is mediated by intestinal and hepatic UGT isoforms like UGT1A1 and UGT1A9. , performed by sulfotransferases (SULTs) such as SULT1A1 and SULT1A3, targets similar phenolic groups, often in competition with . , facilitated by catechol O-methyltransferase (COMT), modifies ortho-dihydroxy () structures on the B-ring, as seen in hesperetin derivatives, further altering . These conjugations occur rapidly during first-pass metabolism, with multiple isoforms contributing to regioselective products. The plays a crucial role in biotransforming unabsorbed or recirculated flavanones in the colon, initiating deglycosylation of glycosylated forms like via bacterial β-glucosidases from genera such as and . Further microbial actions include C-ring fission yielding phenolic acids such as 3-(4-hydroxyphenyl) and 3-(3-hydroxyphenyl) from naringenin and , respectively. These transformations contribute to the diverse metabolite pool entering . In terms of metabolite profiles, conjugated forms predominate in human plasma and following flavanone intake; for example, naringenin-7- and naringenin-4'- are major urinary s, accounting for approximately 4-5% of ingested doses in excretion studies, alongside sulfates and mixed conjugates. These profiles vary interindividually due to polymorphisms but consistently reflect extensive phase II processing over phase I products.

Chemical Synthesis

Classical Synthetic Routes

Classical synthetic routes for flavanones emerged in the early as organic chemists sought to confirm the structures of naturally occurring and synthesize analogs for pharmacological evaluation. These methods relied on fundamental reactions like aldol condensations and intramolecular cyclizations, often starting from readily available phenolic precursors. They were instrumental in establishing the chromanone scaffold of flavanones, despite inefficiencies that spurred later innovations. Seminal work highlighted the reactivity of o-hydroxyaryl ketones, enabling the assembly of the 2-phenyl-2,3-dihydro-4H-chromen-4-one core through stepwise carbon-carbon bond formation and ring closure. The Claisen-Schmidt condensation represents a key historical approach, involving the base-catalyzed condensation of o-hydroxyacetophenone with to generate a 2'-hydroxychalcone intermediate, followed by acid- or base-promoted cyclization to form the flavanone. This sequence proceeds via under alkaline conditions (e.g., NaOH in ), yielding the in moderate efficiency, and subsequent protonation or Michael addition for ring closure. Representative examples include the synthesis of naringenin from 2,4,6-trihydroxyacetophenone and , providing access to citrus-derived flavanones for structural elucidation. While adaptable for substituted variants, the method's two-step nature often results in cumulative losses from chalcone isolation. Overall, these classical routes achieve flavanones in typical overall yields of 40-60%, constrained by the condensation step's equilibrium and cyclization side products like polymeric byproducts or over-oxidation. poses a major limitation, especially with polysubstituted , where ortho-directing effects can favor unwanted isomers or incomplete ring closure, necessitating careful control of reaction conditions. Despite these drawbacks, the methods' simplicity and reliance on inexpensive made them foundational for early 20th-century research, enabling the preparation of key compounds like eriodictyol and for confirmation.

Modern Synthetic Methods

Modern synthetic methods for flavanones have advanced significantly since the early , emphasizing , stereocontrol, and environmental to overcome limitations of classical routes such as low yields and lack of enantioselectivity. These approaches leverage chiral catalysis, integrated reaction sequences, and biological tools to produce flavanones with high purity and , often achieving yields exceeding 80% and enantiomeric excesses () over 90%. Asymmetric synthesis has become a cornerstone for generating enantiopure flavanones, crucial for biological studies due to their stereospecific activities. Chiral metal complexes, particularly (Ru) and (Pd) catalysts, enable enantioselective cyclization through mechanisms like intramolecular oxa-Michael additions or conjugate additions to precursors. For instance, Pd(II)-CarOx complexes catalyze the asymmetric 1,4-addition of arylboronic acids to chromones, yielding (R)-flavanones such as pinostrobin with >90% and up to 99% ee. Similarly, (II)-Noyori-Ikariya complexes facilitate asymmetric transfer hydrogenation-dynamic kinetic resolution (ATH-DKR) of isoflavanones, delivering products with >99% ee in >80% . These methods provide access to specific enantiomers, contrasting with racemic mixtures from traditional acid-catalyzed isomerizations. One-pot methodologies streamline flavanone production by combining chalcone formation and cyclization in a single vessel, reducing purification steps and waste. Microwave-assisted protocols exemplify this efficiency, accelerating Claisen-Schmidt condensation followed by isomerization under basic conditions. In a representative approach, 2-hydroxyacetophenones react with aromatic aldehydes in methanolic KOH under 100 W microwave irradiation for 2 minutes, directly affording functionalized flavanones in 81-94% yields, with electron-donating substituents enhancing selectivity toward cyclized products over chalcones. Polyphosphoric acid (PPA)-promoted variants in DMF/MeOH reflux further demonstrate versatility, converting the same substrates to flavanones in up to 84% yield within 7 hours, suitable for gram-scale synthesis. These tandem processes achieve >80% overall yields, surpassing multi-step classical routes. Recent advances as of 2025 include transition metal-free one-pot syntheses using Cs2CO3-I2 promotion, enabling efficient production of flavanones and flavones from 2-hydroxyacetophenones and aldehydes in high yields without additives. Biocatalytic approaches harness engineered enzymes for stereospecific flavanone synthesis, offering mild conditions and high selectivity. enzymes, particularly from , catalyze the stereospecific cyclization of to (2S)-flavanones in microbial hosts like . Engineered strains expressing alongside chalcone synthase produce pinocembrin at 353 mg/L, with inherent (2S)-stereochemistry, while variants yield pinostrobin (153 mg/L) and other derivatives. applications of these engineered enable scalable, enantiopure production without harsh reagents, aligning with post-2000 advances. Sustainability in modern flavanone synthesis prioritizes green solvents, recyclable catalysts, and reduced energy use, addressing environmental concerns of traditional methods. /reduced oxide (CuO/rGO) nanocomposites serve as heterogeneous catalysts for chalcone-to-flavanone in , delivering 87-96% yields and recyclability over seven cycles without activity loss. catalysts, such as L-proline, promote cyclization in or with >85% yields, minimizing toxic solvents. integration further lowers energy consumption, while biocatalytic systems operate at ambient temperatures, collectively enabling eco-friendly, high-impact production. Additional 2025 developments include N-heterocyclic carbene (NHC) catalysis for aza-flavanones with quaternary stereocenters, expanding sustainable synthetic scope.

Biological Activities and Health Effects

Pharmacological Properties

Flavanones exhibit potent activity primarily through direct scavenging of (ROS) via their phenolic hydroxyl groups, which donate hydrogen atoms or electrons to neutralize free radicals such as and peroxyl radicals. This mechanism is facilitated by the ortho-dihydroxy () configuration in the B-ring, enhancing electron delocalization and stability of the resulting phenoxyl radical. Additionally, flavanones inhibit ROS-generating enzymes, including , by binding to its and preventing substrate oxidation; for instance, naringenin demonstrates mixed-type inhibition with an IC50 of approximately 20 μM. The anti-inflammatory properties of flavanones arise from their ability to modulate key signaling pathways, notably the nuclear factor-kappa B () pathway, where they suppress activation and subsequent p65 subunit translocation to the nucleus. This inhibition reduces the transcription of pro-inflammatory genes, leading to decreased production of cytokines such as tumor necrosis factor-alpha (TNF-α); naringenin, for example, attenuates TNF-α expression in lipopolysaccharide-stimulated macrophages by downregulating activity. Similarly, licoflavanone from licorice inhibits nuclear translocation, thereby lowering TNF-α, interleukin-1β (IL-1β), and IL-6 levels in activated cells. Flavanones also act as inhibitors, targeting pathways involved in and regulation. Naringenin potently inhibits (CYP19), the catalyzing , with an IC50 of 9.2 μM in microsomal assays, potentially through competitive binding at the site. Other examples include inhibition of (COX-2) and inducible nitric oxide synthase (iNOS), where licoflavanone reduces their expression in inflammatory models. Structure-activity relationships reveal that B-ring hydroxylation significantly influences flavanone potency. Increasing the number of hydroxyl groups on the B-ring, particularly at positions 3' and 4', enhances radical scavenging and efficacy by improving hydrogen donation capacity and binding affinity; for instance, eriodictyol (with 3',4'-dihydroxylation) shows greater activity than naringenin (4'-hydroxylation only). Conversely, lack of B-ring , as in pinocembrin, markedly reduces potency in both and inhibitory assays. These metabolic transformations, such as II conjugation, can further modulate active forms generated during .

Potential Therapeutic Applications

Flavanones, particularly those derived from fruits such as naringenin and , have demonstrated potential in mitigating cardiovascular risks through mechanisms that reduce (LDL) oxidation. studies have shown that naringenin enriches LDL particles, thereby increasing their resistance to oxidative damage induced by copper ions or macrophages, which could attenuate the progression of . Meta-analyses of randomized controlled trials indicate that supplementation lowers systolic by 1.4 mmHg (95% CI: -2.7 to -0.02) with no significant effect on diastolic pressure in adults, at doses of 292-1000 mg/day over 3-12 weeks. and studies associate flavanone intake with reductions in . As of 2025, recent studies associate higher flavanone-rich intake with 11-14% lower risks of frailty and poor , and reduced incidence. In the realm of , flavanones exhibit anticancer potential primarily through induction of and inhibition of in various cancer cell lines. has been shown to trigger in cells (e.g., and MDA-MB-231 lines) by modulating activity, downregulating anti-apoptotic proteins like , and activating pathways, with values around 50-100 μM in preclinical models. Similarly, naringenin promotes autophagic cell death and suppresses migration in colorectal and prostate cancer cells via PI3K/Akt pathway inhibition, highlighting its role in preventing . While clinical data remain limited, these mechanisms support the translational potential of flavanones as adjuncts in , with ongoing preclinical evaluations suggesting synergy with chemotherapeutic agents like to enhance efficacy and reduce resistance. For metabolic disorders, flavanones improve and glycemic control, offering promise in . Naringenin enhances insulin signaling in adipocytes and hepatocytes by activating PPARγ and AMPK pathways, reducing in streptozotocin-induced diabetic models at doses of 50-100 mg/kg, with corresponding improvements in blood glucose by 20-30%. A 2023 study demonstrated that naringenin ameliorates diabetic by activating Nrf2 to counteract and , preserving cardiac function in high-fat diet-fed rats. These effects extend to human-relevant models, where flavanone-rich interventions have improved insulin markers like HOMA-IR in overweight individuals with , underscoring their role in delaying onset. Flavanones hold Generally Recognized as Safe (GRAS) status for use in foods, with an ADI of 75 mg/kg bw/day for as affirmed by the FDA for -derived sources. Typical therapeutic doses range from 100-500 mg/day, achieved through supplements or consumption, with clinical trials reporting no significant adverse effects at these levels over 8-12 weeks. Rare side effects are primarily linked to high intake, including potential drug interactions via inhibition by , which may elevate plasma levels of statins or , necessitating caution in patients.

Notable Flavanones

Structural Examples

Flavanones are characterized by a core structure consisting of two phenyl rings (A and B) connected through a heterocyclic ring (C) with a at position 4 and saturation between positions 2 and 3. Representative examples illustrate key structural variations, particularly in patterns and . The parent flavanone compound, naringenin (5,7,4'-trihydroxyflavanone), exemplifies the basic substitution pattern typical of many naturally occurring flavanones. It features hydroxyl groups at positions 5 and 7 on the A ring and at position 4' on the B ring, with the systematic name (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-chromen-4-one, conferring at C-2. This aglycone structure is widespread in fruits and serves as a scaffold for further modifications. Glycosylated forms enhance solubility and bioavailability; a prominent example is hesperidin (hesperetin-7-rutinoside), abundant in oranges. Hesperidin is the 7-O-rutinoside of hesperetin, where hesperetin itself is 5,7-dihydroxy-4'-methoxy-3'-hydroxyflavanone, with the rutinoside (rhamnosyl-glucose) attached at the 7-position of the A ring. This modification distinguishes it from non-glycosylated flavanones like naringenin. Hydroxylation variants further diversify the class. Eriodictyol, with an additional hydroxyl at 3' on the B ring (3',4',5,7-tetrahydroxyflavanone), exhibits the systematic name (2S)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-2,3-dihydro-4H-chromen-4-one and is found in herbs like yerba santa. In contrast, liquiritigenin (4',7-dihydroxyflavanone) lacks the 5-hydroxyl on the A ring, featuring hydroxyls only at 4' on the B ring and 7 on the A ring, with the name 7-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-chromen-4-one, and is isolated from licorice root. Flavanones are distinguished from their isomers, flavanonols, by the absence of a hydroxyl group at position 3 on the C ring; the addition of this 3-hydroxy group in flavanonols, such as , introduces an extra chiral center and alters .

Specific Compounds and Derivatives

Naringin, a flavanone abundant in grapefruit, imparts a characteristic bitter to the fruit and its juices due to its sensory properties. This bitterness arises primarily from naringin's interaction with receptors, making it a key factor in the palatability of products. In processing, naringin undergoes deglycosylation via the enzyme naringinase, which hydrolyzes its rhamnoglucoside moiety to yield the aglycone naringenin, thereby reducing bitterness while preserving nutritional value. Industrial debittering of commonly employs immobilized naringinase in bioreactors, achieving up to 90% removal of naringin and improving juice acceptability without significant loss of other . Hesperetin, the aglycone form of found in fruits, demonstrates neuroprotective effects in preclinical models by attenuating amyloid-beta aggregation and tau hyperphosphorylation. In transgenic mouse models, oral administration of hesperetin at doses of 50-100 mg/kg reduced cognitive deficits and via modulation of Nrf2 and pathways. To address hesperetin's inherent poor aqueous (approximately 48 μg/mL in ), semi-synthetic derivatives such as hesperetin-7-O-glucoside and its sulfonated or iodinated analogs have been developed, exhibiting up to five-fold higher at acidic relevant to gastrointestinal conditions. These modifications enhance rates and potential oral without compromising the core neuroprotective scaffold. Pinocembrin, a prominent flavanone in from honeybees, contributes to the resin's properties through its presence in concentrations up to 4% (40 mg/g) in some European propolis varieties. It exhibits potent antibacterial activity against Gram-positive pathogens, including and , with minimum inhibitory concentrations of 8-16 μg/mL, by disrupting bacterial cell membranes and inhibiting formation. Synthetic analogs of pinocembrin, such as fluorinated or alkylated derivatives, have been explored as drug leads for treating resistant infections, showing enhanced potency against multidrug-resistant strains while maintaining low to mammalian cells. Recent advancements in semi-synthetic flavanone derivatives focus on and forms to boost , addressing the class's typical low absorption rates below 10%. at the 8-position, as in semi-synthetic produced via regioselective lithium chloride-mediated reactions, increases and cellular uptake, with pharmacokinetic studies in rats indicating a 2-3 fold improvement in plasma levels compared to parent flavanones. , particularly chlorination or fluorination on the B-ring using enzymatic halogenases, enhances metabolic stability and membrane permeability; for instance, fluorinated flavanone derivatives demonstrated prolonged half-lives in liver microsomes and up to 50% higher in models. Post-2020 patents and studies highlight these modifications in formulations for targeted therapies, such as analogs for estrogenic applications and ones for uses, emphasizing their role in overcoming flavanone limitations.