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Lactucin
Lactucin
Lactucin
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Lactucin
Names
Preferred IUPAC name
(3aR,4S,9aS,9bR)-4-Hydroxy-9-(hydroxymethyl)-6-methyl-3-methylidene-3,3a,4,5,9a,9b-hexahydroazuleno[4,5-b]furan-2,7-dione
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.440.674 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C15H16O5/c1-6-3-9(17)12-7(2)15(19)20-14(12)13-8(5-16)4-10(18)11(6)13/h4,9,12-14,16-17H,2-3,5H2,1H3/t9-,12-,13+,14+/m1/s1 ☒N
    Key: VJQAFLAZRVKAKM-QQUHWDOBSA-N ☒N
  • InChI=1/C15H16O5/c1-6-3-9(17)12-7(2)15(19)20-14(12)13-8(5-16)4-10(18)11(6)13/h4,9,12-14,16-17H,2-3,5H2,1H3/t9-,12-,13+,14+/m1/s1
    Key: VJQAFLAZRVKAKM-QQUHWDOBBA
  • CC1=C2[C@@H]([C@@H]3[C@@H]([C@@H](C1)O)C(=C)C(=O)O3)C(=CC2=O)CO
Properties
C15H16O5
Molar mass 276.28 g/mol
Appearance White crystalline solid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Lactucin is a bitter substance that forms a white crystalline solid and belongs to the group of sesquiterpene lactones. It is found in some varieties of lettuce and is an ingredient of lactucarium. It is also found in dandelion coffee. It has been shown to have analgesic and sedative properties,[1] which are speculated to occur via modulation of the GABAA receptor,[2] as well as antimalarial activity.[3]

See also

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References

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Lactucin

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from Grokipedia
Lactucin is a guaiane-type sesquiterpene lactone with the molecular formula C15H16O5 and a molar mass of 276.28 g/mol, occurring naturally as a bitter principle in the milky latex of plants such as wild lettuce (Lactuca virosa), garden lettuce (Lactuca sativa), and prickly lettuce (L. serriola), as well as in the roots of chicory (Cichorium intybus). It is a primary active component of lactucarium, the dried latex extract traditionally harvested from Lactuca species and employed in herbal medicine for its sedative and mild narcotic effects. Lactucin manifests as a white crystalline solid with a melting point of 228–233 °C and exhibits solubility in organic solvents like chloroform, dichloromethane, ethyl acetate, and DMSO. Structurally, lactucin is an azulenofuran derivative featuring a hexahydroazuleno[4,5-b]furan core with an exocyclic at position 3, a at position 4, a hydroxymethyl at position 9, and rings at positions 2 and 7, contributing to its reactivity and . These lactones, including lactucin, play a defensive role in against herbivores and pathogens through their bitter and potential . Pharmacologically, lactucin has demonstrated analgesic effects in mice, reducing pain responses in hot-plate and tail-flick tests at doses of 15–30 mg/kg, with potency comparable to ibuprofen. It also induces sedation by decreasing locomotor activity at similar doses and shows anti-inflammatory potential by modulating immune responses. Further research highlights its antimalarial activity against Plasmodium falciparum in vitro, as well as inhibitory effects on cancer cell proliferation through downregulation of MAPK signaling and central carbon metabolism pathways. These properties underscore lactucin's relevance in both ethnopharmacology and modern therapeutic exploration.

Chemistry

Structure and nomenclature

Lactucin is a characterized by the molecular formula C15_{15}H16_{16}O5_{5}. Its systematic classification places it within the guaianolide subgroup of , which are secondary metabolites featuring a 15-carbon backbone. These compounds typically exhibit a fused ring system derived from , with lactucin specifically structured as an derivative. The for lactucin is (3aR,4S,9aS,9bR)-4-hydroxy-9-(hydroxymethyl)-6-methyl-3-methylidene-3,3a,4,5,9a,9b-hexahydroazuleno[4,5-b]furan-2,7-dione. This reflects its core architecture: a γ-butyrolactone ring fused to a hydroazulene skeleton, where the moiety consists of a seven-membered ring fused to a five-membered ring, partially saturated in the hexahydro form. The at the four chiral centers is specified as 3aR, 4S, 9aS, and 9bR, which dictates the three-dimensional arrangement essential to its molecular identity. Key structural features include an exocyclic at position 3 (3-methylidene), a hydroxyl at C-4, a at C-9, and a at C-6, alongside the system with and functionalities at C-2 and C-7, respectively. The α-methylene-γ- moiety—formed by the conjugation of the exocyclic methylene to the γ- carbonyl—is a defining element of lactucin's and underpins its reactivity profile. This motif, common in guaianolides, consists of the unsaturated ring (O=C-O-CH2_2-C=CH2_2) integrated into the bicyclic framework.

Physical and chemical properties

Lactucin appears as a crystalline solid. It has a of 276.28 g/mol and a of 228–233 °C. Lactucin shows limited in , with estimated values ranging from approximately 7 to 71 g/L at 25 °C depending on predictive models, but it is readily soluble in organic solvents such as , , , , acetone, and DMSO. In terms of stability, lactucin is sensitive to light, undergoing UV-induced degradation via hydration of its C(1)–C(10) double bond with a half-life of about 45 minutes under irradiation, independent of temperature in the range of 20–40 °C. It is also unstable in alkaline conditions, where treatment can result in over 99% degradation due to hydrolysis of the lactone ring. Lactucin exhibits moderate thermal stability, consistent with its high melting point. Chemically, lactucin possesses reactivity at its α-methylene-γ-lactone moiety, enabling Michael-type addition reactions with nucleophiles such as thiols or amines, a feature linked to its electrophilic nature. Key spectroscopic properties include a UV absorption maximum at 257 nm (ε = 14,000), indicative of its conjugated enone system. The displays a characteristic γ-lactone carbonyl stretch around 1770 cm⁻¹, along with bands for hydroxyl (≈3400 cm⁻¹) and α,β-unsaturated (≈1660 cm⁻¹) functionalities, as typical for lactones.

Natural occurrence

Plant sources

Lactucin is primarily found in of the Lactuca within the family, particularly in Lactuca virosa (wild ) and Lactuca sativa (garden ), where it occurs as a in the milky latex known as . In L. virosa, lactucin derivatives such as lactucin-15-oxalate are abundant in the latex, reaching concentrations of approximately 40.7 mg/ml. Similarly, in L. sativa cultivars like 'Diana', total s, including lactucin conjugates, can accumulate to 147.1 mg/ml in latex during the bolting stage. Other notable sources include Cichorium intybus (chicory), where lactucin is present in leaves at levels up to 350 mg/kg dry weight, alongside derivatives like 8-deoxylactucin (598 mg/kg dry weight). In Taraxacum officinale (common dandelion), lactucin has been identified in roots and leaves, contributing to its bitter profile. Concentrations vary by species, plant part, cultivar, and environmental factors such as UV exposure, which can elevate sesquiterpene lactone levels in lettuce and chicory. Within , lactucin is concentrated in the of stems and leaves, released upon wounding, with lower amounts in and aerial parts; it is notably scarce in seeds. It co-occurs with related compounds such as and 11β,13-dihydrolactucin, enhancing the overall bitter and bioactive properties of the . Historically, lactucin has been extracted from as a key bitter principle in substitutes and from dandelion in herbal preparations, though modern analyses confirm its presence across these plant materials.

Biosynthesis in plants

Lactucin, a guaianolide sesquiterpene lactone, is biosynthesized in plants primarily through the cytosolic mevalonate pathway, which produces farnesyl pyrophosphate (FPP) from acetyl-CoA units as the universal precursor for sesquiterpenes. FPP is then cyclized to form germacrene A by germacrene A synthase (GAS), initiating the sesquiterpene skeleton. Subsequent oxidation steps involve germacrene A oxidase (GAO) to yield germacrene A alcohol, followed by further dehydrogenation to the carboxylic acid form, and cyclization mediated by costunolide synthase (COS) and kauniolide synthase (KLS) to produce kauniolide, a key intermediate. From kauniolide, uncharacterized enzymes facilitate rearrangement to 8-deoxylactucin, which is then hydroxylated at the C-8 position by lactucin synthase (LCS, a cytochrome P450 enzyme CYP71DD33) to form lactucin. This pathway is conserved across Asteraceae species, with the final lactone ring closure occurring via enzymatic oxidation and cyclization. Isotopic labeling studies using [1-¹³C]-, [2-¹³C]-, and [1,2-¹³C₂]-acetate in hairy root cultures of Lactuca floridana have confirmed the incorporation of acetate units into lactucin derivatives, as evidenced by ¹³C-NMR enrichment patterns aligning with the acetate-mevalonate-germacradiene route. These results demonstrate that the carbon skeleton of lactucin originates from multiple acetate molecules, supporting the mevalonate pathway's role in providing the isoprenoid building blocks. Genes encoding key enzymes in lactucin biosynthesis, such as CiLCS, are predominantly expressed in specialized laticifer tissues where sesquiterpene lactones accumulate. is upregulated in response to biotic stresses like herbivory, mediated by signaling hormones such as , which enhance the production of defense-related sesquiterpene lactones in . This regulation positions lactucin as a stress-inducible compound contributing to defense. In an evolutionary context, lactucin's is part of the broader of the family, where over 5,000 structures have diversified through gene duplications and enzymatic modifications since the family's divergence. These compounds, including lactucin, evolved primarily as anti-herbivory agents due to their bitter taste, deterring feeding by insects and mammals while providing ecological advantages in natural environments.

Pharmacology

Sedative and analgesic effects

Lactucin, a found in various species, exerts effects primarily through its interaction with GABA_A receptors. It binds to the benzodiazepine site on these receptors with high affinity (approximately 80.7%), enhancing chloride ion influx and promoting neuronal hyperpolarization, which leads to a calming and anxiolytic-like response milder than that of full agonists. This partial contributes to reduced spontaneous locomotor activity in animal models, as demonstrated in mice where lactucin at 30 mg/kg decreased activity in behavioral assays. The properties of lactucin have been observed in models using hot-plate and tail-flick tests, indicating both central and peripheral relief mechanisms. These effects may involve inhibition of synthesis, akin to non-steroidal drugs, or modulation of pathways through indirect enhancement of endogenous enkephalins via enkephalinase inhibition in related plant extracts. In mice, lactucin administered at 15-30 mg/kg produced comparable to ibuprofen at 30-60 mg/kg, with no significant involvement of receptors directly implicated in the isolated compound's action. Dosage studies in mice highlight lactucin's efficacy for at 15-30 mg/kg. Traditional uses of wild lettuce () extracts, rich in lactucin, have long included remedies for and mild pain, often as a safer alternative to due to its low potential and absence of strong mu-opioid receptor affinity. Key research, such as Wesołowska et al. (2006), underscores these properties through assays, supporting lactucin's role as a mild without notable tolerance development in preliminary observations.

Anti-inflammatory and antimicrobial activities

Lactucin, a found in plants of the family, exhibits anti-inflammatory effects primarily through modulation of key signaling pathways involved in immune responses. It inhibits the pathway by regulating upstream mediators such as TLR4-MyD88-MAPK signaling, which reduces the translocation of subunits to the nucleus and subsequent transcription of pro-inflammatory genes. Additionally, the α-methylene-γ-lactone moiety in lactucin's structure enables alkylating activity via Michael addition to nucleophilic sites on proteins, contributing to its suppression of inflammatory cascades. In cellular models, lactucin downregulates production, notably reducing IL-6 levels in LPS-stimulated RAW264.7 macrophages at concentrations of 25–50 μM, while effects on TNF-α are less consistent across studies. Lactucin's antimicrobial properties include notable antimalarial activity against , as demonstrated in bioassays using the HB3 clone of the Honduras-1 strain. In the seminal study by Bischoff et al., lactucin isolated from intybus roots achieved complete inhibition of parasitemia at 10 μg/mL after 48 hours, validating traditional uses of for malaria-like fevers. It also displays moderate antibacterial effects against Gram-positive pathogens, such as , where pure lactucin acts as a weak growth inhibitor, though less potent than related compounds like . Synergistic interactions enhance lactucin's bioactivity when combined with , another co-occurring in plant extracts. Mixtures from species show amplified and effects, likely due to complementary inhibition of release and microbial proliferation. Recent models, including LPS-induced in gut-liver axis simulations, further confirm these combined effects in reducing hepatic and .

Research and applications

Anticancer potential

Lactucin, a derived from plants such as Cichorium intybus, has shown promising anticancer activity in preclinical studies, primarily through induction of and disruption of proliferation pathways. As part of the broader class of lactones, these compounds exert effects leading to and inhibition of cancer signaling cascades. The primary mechanism involves the generation of (ROS) and activation of , promoting . In human renal carcinoma Caki-1 cells, lactucin treatment dose-dependently induced by downregulating anti-apoptotic proteins and CFLARL, with ROS mediating the inactivation of and subsequent activation. Additionally, lactucin causes arrest, notably at the G0/, as observed in lung adenocarcinoma models where it upregulated and p21 while downregulating cyclins and CDKs. In vitro studies demonstrate against various lines, including (HL-60), renal (Caki-1), and (A549, H2347), with IC50 values ranging from approximately 69–80 μM in cells after 48 hours. Notably, lactucin exhibits selectivity, inhibiting proliferation in s while sparing normal fibroblasts (MRC-5) at similar concentrations. In HL-60 cells, doses of 25–100 μM induced sub-G1 and morphological changes indicative of , such as condensation and apoptotic body formation. Key investigations, including Jang et al. (2021) on ROS-mediated in renal cells and Imam et al. (2022) on MAPK and downregulation in cells, underscore these antitumor properties. Despite these findings, lactucin's clinical translation is limited by its low aqueous solubility and poor bioavailability, challenges common to sesquiterpene lactones, with nanoformulations demonstrated for related compounds like parthenolide to improve tumor targeting and reduce systemic exposure.

Historical and modern uses

Lactucin, a sesquiterpene lactone found in the latex of various Lactuca species, has been utilized historically for its sedative properties. In ancient Greek and Roman medicine, the milky sap from lettuce plants, containing lactucin, was employed as a sedative and pain reliever, with references dating back to the first century. During the 19th century, the dried latex known as lactucarium was harvested from wild lettuce (Lactuca virosa) and prescribed as a milder alternative to opium for sedation and analgesia, particularly in Europe and America, due to its perceived lack of addictive potential and fewer side effects. In modern contexts, lactucin is incorporated into herbal supplements derived from wild lettuce extracts for potential relief and relaxation, often marketed as natural remedies for mild aches, anxiety, and disturbances, though clinical remains limited. Extracts from (Cichorium intybus), rich in lactucin, have been explored for antimalarial applications, with studies identifying lactucin and its derivative as active compounds inhibiting Plasmodium falciparum growth , suggesting potential for development into novel therapies against . Lactucin exhibits a favorable safety profile, with low demonstrated in animal models; for instance, ethanolic extracts of intybus containing lactucin have an oral LD50 exceeding 4000 mg/kg in rats, indicating minimal risk at therapeutic doses. Common side effects are mild and include drowsiness, which aligns with its effects, as well as occasional gastrointestinal upset such as or when consumed in higher amounts. Lactucin is not approved by the FDA as a pharmaceutical and is instead available as a in forms like wild teas or , where manufacturers typically include dosage warnings to avoid exceeding recommended amounts (e.g., 12–24 drops of two to three times daily) due to risks of or in overdose. A 2024 study demonstrated lactucin's potential in reversing liver in mouse models by inhibiting TGF-β1/ signaling, reducing and collagen deposition, highlighting additional therapeutic applications beyond anticancer effects. Future research directions emphasize the need for clinical trials to standardize lactucin extraction and dosing for reliable , particularly in and antimalarial applications, alongside investigations into synergistic combinations with other sesquiterpenes like to enhance therapeutic outcomes without increasing .

References

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