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Lactucopicrin
View on Wikipediafrom Wikipedia
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| Names | |
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| Preferred IUPAC name
[(3aR,4S,9aS,9bR)-4-Hydroxy-6-methyl-3-methylidene-2,7-dioxo-2,3,3a,4,5,7,9a,9b-octahydroazuleno[4,5-b]furan-9-yl]methyl (4-hydroxyphenyl)acetate | |
| Other names
Intybin
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| Identifiers | |
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3D model (JSmol)
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| ChemSpider |
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| MeSH | Intybin |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties | |
| C23H22O7 | |
| Molar mass | 410.422 g·mol−1 |
| Pharmacology | |
| Oral, Smoked | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Lactucopicrin (Intybin) is a bitter substance that has a sedative and analgesic effect,[1] acting on the central nervous system. It is a sesquiterpene lactone, and is a component of lactucarium, derived from the plant Lactuca virosa (wild lettuce), as well as being found in some related plants such as Cichorium intybus.[2] It is also found in dandelion coffee.
As well as their traditional use as sedatives and analgesics, these plants have also been used as antimalarials, and both lactucin and lactucopicrin have demonstrated antimalarial effects in vitro.[3] Lactucopicrin has also been shown to act as an acetylcholinesterase inhibitor.[4]
See also
[edit]References
[edit]- ^ Wesołowska, A; Nikiforuk, A; Michalska, K; Kisiel, W; Chojnacka-Wójcik, E (Sep 2006). "Analgesic and sedative activities of lactucin and some lactucin-like guaianolides in mice". Journal of Ethnopharmacology. 107 (2): 254–8. doi:10.1016/j.jep.2006.03.003. PMID 16621374.
- ^ Sessa, RA; Bennett, MH; Lewis, MJ; Mansfield, JW; Beale, MH (Sep 2000). "Metabolite profiling of sesquiterpene lactones from Lactuca species. Major latex components are novel oxalate and sulfate conjugates of lactucin and its derivatives". Journal of Biological Chemistry. 275 (35): 26877–84. doi:10.1074/jbc.M000244200. PMID 10858433.
- ^ Bischoff, TA; Kelley, CJ; Karchesy, Y; Laurantos, M; Nguyen-Dinh, P; Arefi, AG (2004). "Antimalarial activity of lactucin and lactucopicrin: sesquiterpene lactones isolated from Cichorium intybus L.". Journal of Ethnopharmacology. 95 (2–3): 455–7. doi:10.1016/j.jep.2004.06.031. PMID 15507374.
- ^ Rollinger, JM; Mocka, P; Zidorn, C; Ellmerer, EP; Langer, T; Stuppner, H (2005). "Application of the in combo screening approach for the discovery of non-alkaloid acetylcholinesterase inhibitors from Cichorium intybus". Current Drug Discovery Technologies. 2 (3): 185–93. doi:10.2174/1570163054866855. PMID 16472227.
Lactucopicrin
View on Grokipediafrom Grokipedia
Chemical characteristics
Molecular structure
Lactucopicrin is classified as a guaianolide-type sesquiterpene lactone, characterized by a bicyclic guaiane skeleton fused to a γ-lactone ring and bearing an exocyclic methylene group at the α-position of the lactone.[9] This structural motif is typical of many bioactive sesquiterpene lactones found in the Asteraceae family.[10] The molecular formula of lactucopicrin is CHO, with an exact mass of 410.1366 Da. Its systematic IUPAC name is [(3aR,4S,9aS,9bR)-4-hydroxy-6-methyl-3-methylidene-2,7-dioxo-4,5,9a,9b-tetrahydro-3aH-azuleno[8,7-b]furan-9-yl]methyl 2-(4-hydroxyphenyl)acetate. Key functional groups in the molecule include the α-methylene-γ-lactone, which contributes to its reactivity; an α,β-unsaturated ketone (enone) in the seven-membered ring; a phenolic ester side chain attached at the C-9 position; and a hydroxyl group at C-4. The stereochemistry features specific configurations at the four chiral centers: 3aR, 4S, 9aS, and 9bR, which define the overall three-dimensional architecture. The molecular structure is often depicted using the canonical SMILES notation: CC1=C2C@@HC(=CC2=O)COC(=O)CC4=CC=C(C=C4)O, illustrating the fused ring system, exocyclic double bond, and ester linkage. Lactucopicrin shares a core scaffold with lactucin, its biosynthetic precursor, differing primarily by the addition of the phenolic ester moiety.[9]Physical and chemical properties
Lactucopicrin appears as a white to off-white solid at room temperature.[12] It melts at 146 °C.[12] The compound exhibits low solubility in water, estimated at approximately 3.78 g/L at 25 °C, reflecting its moderate lipophilicity indicated by a logP value of 1.1.[13][1] In contrast, lactucopicrin is readily soluble in organic solvents, including dimethyl sulfoxide (up to 250 mg/mL), ethanol, chloroform, and ethyl acetate.[14] Key spectroscopic characteristics support its structural identification. Infrared (IR) spectroscopy reveals a prominent absorption band at around 1760 cm⁻¹ attributable to the carbonyl stretch of the γ-lactone ring, typical for sesquiterpene lactones.[15] Nuclear magnetic resonance (NMR) data, including ¹H and ¹³C spectra, confirm the presence of the α-methylene-γ-lactone moiety and the phenolic ester, with characteristic signals for the exocyclic methylene protons around δ 6.2–6.3 ppm and the aromatic protons of the p-hydroxyphenylacetate group between δ 7.0–7.4 ppm.[16] Ultraviolet (UV) absorption occurs near 220 nm due to the conjugated systems in the molecule.[17] Regarding chemical stability, lactucopicrin is susceptible to base-catalyzed hydrolysis of its ester linkage, converting it to lactucin under alkaline conditions.[9] The α-methylene group adjacent to the lactone carbonyl exhibits reactivity in Michael addition reactions with nucleophiles such as thiols, a common feature enabling its biological interactions.[18] The phenolic hydroxyl group has a predicted pKa of approximately 9.8, facilitating deprotonation in basic environments, while no other significantly ionizable groups are present.[12]Natural sources and biosynthesis
Occurrence in plants
Lactucopicrin is a sesquiterpene lactone primarily occurring in the latex of wild lettuce (Lactuca virosa), where it is one of the major bitter compounds contributing to the plant's chemical defense.[19] This compound is concentrated in the specialized lactifer cells, which form milky channels throughout the plant, particularly in stems and leaves, and is released upon tissue damage to deter herbivores and pathogens through its intense bitterness and potential toxicity.[20] In L. virosa, lactucopicrin levels are notably higher compared to domesticated relatives, reflecting adaptations in wild varieties for enhanced protection against environmental stresses.[20] The compound is also present in chicory (Cichorium intybus), especially in root extracts and leaf tissues, where it serves a similar ecological role as a defense mechanism.[21] Total sesquiterpene lactone concentrations, including lactucopicrin, in chicory leaves vary widely across germplasm, ranging from 383 to 2497 mg/kg dry matter, with higher levels often observed in stressed or specific cultivars.[22] In cultivated lettuce (Lactuca sativa), lactucopicrin occurs at lower levels primarily in leaves and seeds, with averages around 586 µg/g dry weight in diverse germplasm collections and up to 1448 µg/g extract in certain green varieties.[23][24] Lactucopicrin frequently co-occurs with related sesquiterpene lactones such as lactucin and 11,13-dihydrolactucopicrin, particularly in latex and root tissues, enhancing the overall defensive profile of these plants.[20] Quantification of these compounds typically relies on high-performance liquid chromatography (HPLC) methods, which allow precise measurement of variations influenced by factors like plant age, stress, and domestication status.[23]Biosynthetic pathway
The biosynthesis of lactucopicrin begins with the mevalonate pathway-derived precursor farnesyl pyrophosphate (FPP), which is cyclized to germacrene A by germacrene A synthase (GAS), an enzyme encoded by genes such as LsGAS1 and LsGAS2 in Lactuca sativa. This initial step establishes the germacrane skeleton characteristic of many sesquiterpene lactones in the Asteraceae family. Subsequent oxidation of germacrene A to germacrene A acid (GAA) is catalyzed by germacrene A oxidase (GAO), a cytochrome P450 enzyme (CYP71AV subfamily), with homologs like LsGAO identified in lettuce. The carboxylic acid group in GAA then undergoes regioselective hydroxylation and lactonization by costunolide synthase (COS, CYP71BL2, encoded by LsCOS in L. sativa), yielding costunolide, a central intermediate in sesquiterpene lactone pathways.[25] From costunolide, the pathway proceeds toward the guaiane skeleton required for lactucopicrin through epoxidation and cyclization steps. Costunolide is first converted to kauniolide by kauniolide synthase (KLS, CYP71BZ6X), followed by sequential oxidations to 8-deoxylactucin via unidentified enzymes. Hydroxylation at the 8α position transforms 8-deoxylactucin to lactucin, mediated by lactucin synthase (LCS, CYP71DD33, encoded by CiLCS in related Cichorium intybus and homologs in Lactuca).[25] The final step involves esterification at the C15 position of lactucin with 4-hydroxyphenylacetic acid, catalyzed by an acyltransferase, to introduce the characteristic side chain and form lactucopicrin; this process also includes methylene introduction at relevant positions through dehydrogenase activity, such as germacrene A alcohol dehydrogenase (potentially LsGLDH in L. sativa).[26] Earlier dehydrogenation steps, including oxidation of germacrene A alcohol intermediates to acids, are facilitated by NADP+-dependent dehydrogenases.[26] Genetically, the pathway is encoded by clustered or co-expressed genes in Lactuca species, including LsCOS for lactone formation and homologs of CiLCS for late-stage modifications, with expression primarily in laticifers and roots.[25] Regulation occurs through stress hormones like jasmonic acid, where methyl jasmonate treatment upregulates GAS, GAO, and COS transcripts, enhancing flux toward lactucopicrin under environmental stresses such as wounding or UV exposure. Evolutionarily, the lactucopicrin pathway derives from ancestral sesquiterpene pathways in the Asteraceae family, with GAS and GAO homologs present in basal subfamilies like Barnadesioideae, reflecting gene duplications that diversified lactone structures across the clade.Biological and pharmacological activities
Central nervous system effects
Lactucopicrin exhibits sedative effects primarily through its interaction with the central nervous system, acting as a modulator of γ-aminobutyric acid type A (GABA_A) receptors, similar to benzodiazepines.[27] In vitro studies demonstrate that lactucopicrin binds to the GABA_A-benzodiazepine (BDZ) receptor with an affinity of 55.9 ± 0.7%, inhibiting [³H]-flumazenil binding in a concentration-dependent manner.[28] This binding promotes GABAergic neurotransmission, leading to dose-dependent hypnotic effects in animal models; for instance, administration of green romaine lettuce extract containing lactucopicrin at 100 mg/kg orally increased sleep duration by approximately 80 minutes and reduced sleep latency in pentobarbital-induced sleep mice.[28] In spontaneous locomotor activity tests, lactucopicrin at 30 mg/kg reduced mouse activity by 43%, indicating central sedative properties without affecting peripheral coordination.[29] The compound also possesses analgesic properties, inhibiting pain responses through modulation of central pathways, including potential interference with prostaglandin synthesis and opioid receptor interactions.[30] In hot plate tests assessing thermal nociception, lactucopicrin at doses of 15 and 30 mg/kg produced analgesic effects comparable to ibuprofen at 30 mg/kg, with lactucopicrin identified as the most potent among related guaianolides.[29] Similarly, in tail-flick tests, a 30 mg/kg dose of lactucopicrin yielded analgesia equivalent to 60 mg/kg of ibuprofen, highlighting its efficacy at lower doses.[30] These effects contribute to its role in traditional remedies derived from wild lettuce (Lactuca virosa), where lactucopicrin is a key component of "lettuce opium," historically used in Europe for centuries to alleviate insomnia and pain due to its combined sedative and analgesic actions.[24] Preclinical evidence suggests lactucopicrin's potential for mild anxiolytic effects via GABA_A receptor modulation, offering sleep promotion and anxiety reduction in rodent models without the respiratory depression associated with opioids.[27] In caffeine-induced insomnia models, extracts rich in lactucopicrin extended non-REM sleep and decreased wakefulness, supporting its utility in addressing sleep disturbances linked to anxiety.[28] This profile positions lactucopicrin as a candidate for CNS-targeted therapies, though human clinical data remain limited.Anti-inflammatory and immunomodulatory effects
Lactucopicrin exhibits anti-inflammatory effects primarily through inhibition of the NF-κB signaling pathway. In tumor necrosis factor-α (TNF-α)-stimulated human and mouse aortic endothelial cells, it dose-dependently suppresses NF-κB activation by downregulating importin-α3 expression, which disrupts the nuclear translocation of NF-κB subunits.[31] This mechanism reduces TNF-α-induced expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), thereby limiting monocyte adhesion to endothelial cells and attenuating vascular inflammation.[31] Lactucopicrin also modulates the aryl hydrocarbon receptor (AHR) pathway, antagonizing its crosstalk with NF-κB in macrophages and intestinal epithelial cells. In TNF-α-induced inflammation models, it acts as an AHR modulator, with silencing of AHR expression attenuating its inhibitory effects on NF-κB, highlighting a novel regulatory interaction that suppresses inflammatory responses in these cell types.[32] In vivo studies demonstrate lactucopicrin's efficacy in reducing inflammation. Lactucopicrin-rich extracts from Cichorium intybus roots attenuate carrageenan-induced paw edema in rats, with significant inhibition observed at doses of 50–100 mg/kg.[33] Additionally, oral administration of such extracts provides gastroprotection against ethanol-induced gastric ulcers in rat models by preserving mucosal integrity and reducing lesion severity.[34] Regarding immunomodulation, lactucopicrin selectively suppresses pro-inflammatory cytokines in lipopolysaccharide-stimulated macrophages. It represses the expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and TNF-α without altering levels of the anti-inflammatory cytokine IL-10.[35] Lactucopicrin exhibits antioxidant activity by scavenging reactive oxygen species (ROS) and activating the NRF2 pathway to mitigate oxidative stress in cellular models.[36] This ROS-scavenging activity, potentially linked to its structural features including the α-methylene-γ-lactone moiety, complements its anti-inflammatory actions by preventing cellular damage.[36]Other pharmacological properties
Lactucopicrin exhibits hepatoprotective properties by promoting the β-oxidation of fatty acids and reducing lipid accumulation in models of non-alcoholic fatty liver disease (NAFLD). In free fatty acid (FFA)-induced HepG2 cells, treatment with 20 μM lactucopicrin significantly decreased triglyceride content and lipid droplet formation, as evidenced by Oil Red O staining and biochemical assays (p < 0.0001). This effect is mediated through upregulation of hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase trifunctional protein (HADHA) expression at both gene and protein levels, enhancing mitochondrial β-oxidation. Additionally, pathway analysis revealed activation of peroxisome proliferator-activated receptor alpha (PPARα), contributing to improved lipid metabolism in hepatic cells.[37] In antimicrobial contexts, lactucopicrin demonstrates antimalarial activity against the HB3 clone of Plasmodium falciparum (Honduras-1 strain), as identified from bioassay-guided isolation of sesquiterpene lactones from Cichorium intybus roots. This compound, along with related lactones, was highlighted for its potential based on traditional use of chicory extracts in malaria treatment.[38] Regarding anticancer effects, lactucopicrin induces apoptosis in various cancer cell lines. In human skin melanoma SK-MEL-5 cells, it promotes Bax upregulation, G2/M cell cycle arrest, and downregulation of miR-101, leading to reduced cell viability and increased apoptotic markers. Similarly, in Saos-2 osteosarcoma cells, lactucopicrin inhibits proliferation by disrupting cell migration, invasion, and inducing sub-G1 phase arrest, suggesting potential as an antiproliferative agent. These mechanisms highlight its role in caspase-mediated apoptosis pathways.[39][40] Lactucopicrin also displays hypolipidemic and metabolic benefits, including limitation of oxidized low-density lipoprotein (oxLDL) uptake in macrophages, which reduces foam cell formation and cardiovascular risk. At physiologically relevant concentrations, it selectively decreases lectin-like oxLDL receptor-1 (LOX-1) in lipid rafts, inhibiting cholesterol influx (p < 0.05). In high-fat diet-fed mice, lactucopicrin ameliorates obesity by promoting white adipose tissue browning via the AMPK/SIRT1/PGC-1α pathway, resulting in reduced body weight and improved metabolic parameters, including enhanced insulin sensitivity. No genotoxicity has been reported for lactucopicrin, and related plant extracts show low acute oral toxicity with LD50 values exceeding 4000 mg/kg in rats.[41][42][43]History and research
Discovery and isolation
Lactucopicrin, a sesquiterpene lactone also known by the synonym intybin, was first identified as one of the bitter principles in the milky latex of wild lettuce (Lactuca virosa), known as lactucarium, which has been collected and used medicinally since the mid-19th century.[44] The latex was traditionally obtained by incising the stems of mature plants and drying the exuded fluid, but early efforts to isolate active alkaloids were unsuccessful until the 20th century. A comprehensive pharmacological study published in 1911 revealed that the fresh latex contained two key bitter principles responsible for its sedative and analgesic properties: lactucin and lactucopicrin.[45] These compounds were characterized as the primary contributors to the central nervous system effects observed in lactucarium preparations. Lactucopicrin was noted for its potent bitterness and light sensitivity, distinguishing it from other components.[38] The full chemical structure of lactucopicrin was elucidated in the 1970s through advanced spectroscopic techniques, including X-ray crystallography, confirming its guaianolide sesquiterpene lactone framework.[9] This structural determination enabled subsequent revisions and identifications of related derivatives in various Asteraceae species. Traditional isolation methods relied on ethanol extraction of the dried latex, followed by precipitation and basic fractionation to yield the bitter fraction containing lactucopicrin.[2] Modern techniques have improved efficiency and purity; for instance, supercritical CO₂ extraction from chicory (Cichorium intybus) roots, combined with high-performance liquid chromatography (HPLC) purification, allows for selective recovery of lactucopicrin with reported yields of approximately 0.09% for sesquiterpene lactones from root material.[46][47] These methods minimize solvent use and preserve the compound's bioactivity. A significant milestone in lactucopicrin research occurred in 2004, when isolates from C. intybus were tested and confirmed to exhibit antimalarial activity against Plasmodium falciparum, highlighting its potential beyond traditional uses.[38] The compound's nomenclature includes the synonym intybin, reflecting its early identification in chicory, with the CAS number 65725-11-3 assigned in the 1980s for standardized reference.[48]Modern studies and potential applications
Recent research has highlighted lactucopicrin's role in modulating key inflammatory pathways, with a 2021 study in Biochemical Pharmacology demonstrating its inhibition of importin-α3-mediated NF-κB activation in inflamed endothelial cells, leading to reduced sepsis severity in mouse models.[49] This mechanism suggests lactucopicrin's potential as a dietary anti-inflammatory agent. Similarly, a 2023 investigation in the Journal of Agricultural and Food Chemistry explored biosynthetic engineering in chicory (Cichorium intybus), where inactivation of lactucin synthase increased accumulation of anti-inflammatory precursors like 8-deoxylactucin, indirectly enhancing lactucopicrin-related sesquiterpene lactone production for potential therapeutic extraction.[46] A 2025 study in the Journal of Medicinal Chemistry further elucidated lactucopicrin's modulation of the crosstalk between NF-κB and aryl hydrocarbon receptor (AHR) pathways in TNFα-induced inflammation models across macrophages, endothelial, and intestinal epithelial cells, positioning it as a potent NF-κB antagonist and novel AHR modulator.[32] Therapeutically, lactucopicrin shows promise as a drug candidate for inflammatory bowel disease (IBD), with a 2025 Molecular Nutrition & Food Research paper reporting its enhancement of apoptotic cell clearance by colonic epithelial cells, suppressing colitis in mouse models via reduced inflammation.[50] For non-alcoholic fatty liver disease (NAFLD), a 2022 study indicated that lactucopicrin ameliorates free fatty acid-induced steatosis in HepG2 cells by regulating lipid metabolism genes like HADHA and ADAM17.[51] Its antimalarial activity, confirmed against Plasmodium falciparum in earlier work but reinforced in modern contexts, supports exploration as an adjunct therapy.[52] As a dietary supplement derived from lettuce, lactucopicrin contributes to anti-inflammatory benefits, with intake from leafy greens linked to lower systemic inflammation markers in observational data.[53] In agriculture, breeding efforts target elevated lactucopicrin levels in lettuce (Lactuca sativa) to bolster pest resistance, as sesquiterpene lactones like lactucopicrin act as defensive allelochemicals against insects such as aphids and leafminers, with genetic mapping identifying QTLs for higher content in resistant varieties.[54] However, challenges include lactucopicrin's low oral bioavailability due to poor solubility and rapid metabolism, prompting post-2020 research into nanoparticle delivery systems to improve targeted absorption and efficacy in inflammatory models.[55] Future directions encompass clinical trials evaluating lactucopicrin for pain management, building on its sedative properties observed in preclinical CNS studies. Additionally, a 2024 PMC study revealed lactucopicrin's promotion of fatty acid β-oxidation via AMPK activation, attenuating lipid accumulation in hepatocytes and suggesting expanded applications in metabolic disorders.[56]References
- https://pubchem.ncbi.nlm.nih.gov/compound/Lactucopicrin