Lactones

Other Names

1-oxacycloalkan-2-oneAlpha-methylene-gamma-lactonesAmbrosanolidesBeta-lactonesButyrolactonesCadinanolidesCaprolactonesCoumarin (benzenoid lactone)Cyclic estersCyclic esters of hydroxy carboxylic acidsDelta-lactonesDiterpene lactonesElemanolidesEpsilon-lactonesEremophilanolidesEudesmanolidesGamma-lactonesGermacranolidesGuaianolidesHeliangolidesHydroxy acid lactonesIntramolecular estersMacrocyclic lactonesMacrolactonesMacrolidesMonoterpene lactonesPseudoguaianolidesPsilostachyanolidesResorcylic acid lactonesSesquiterpene lactonesSesquiterpenoids (lactone-bearing)StrigolactonesTriterpene lactonesValerolactonesXanthanolides

Synopsis

Lactones: A Comprehensive Reference on Natural Lactone Compounds as Dietary Supplements and Medicinal Ingredients

1. Identity, Chemical Definition, and Classification

Lactones are cyclic carboxylic esters. More specifically, a lactone is an ester in which the functional group of the ester has become part of a ring structure with carbon atoms. The lactone structural motif is defined by the intramolecular esterification of a hydroxy acid, in which the carbonyl carbon and the ring oxygen are both incorporated into the cyclic backbone. The term "lactones" encompasses any organic chemicals having a five-member ring lactone structure in which the oxygen atom of the C=O group can be replaced by a sulfur atom or a nitrogen grouping.

Lactones are classified primarily by the size of their ring and by the position of the oxygen atom relative to the carbonyl group. The Greek letter system is used to denote ring size: alpha (α), beta (β), gamma (γ), delta (δ), and larger macrocyclic forms. Five-membered γ-lactones and six-membered δ-lactones are prevalent; β-lactones appear in a number of natural products. Ten-membered lactones are an important class of naturally occurring phytotoxic lactones; examples include Herbarumin I and Stagonolide A. Macrocyclic lactones are also important natural products.

In the context of dietary supplements and natural health products, the most pharmacologically important lactone subclasses are:

Sesquiterpene lactones (STLs): Sesquiterpene lactones (STLs) are a prominent group of plant secondary metabolites predominantly found in the Asteraceae family and have multiple ecological roles and medicinal applications.
Diterpene lactones: Exemplified by andrographolide from Andrographis paniculata.
γ-Butyrolactones: γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules.
Macrolide lactones: Including avermectins and macrolide antibiotics.

Sesquiterpene lactones (STLs) are one of the largest biogenetically homogenous groups of natural products known. Currently, the Dictionary of Natural Products holds a total of over 11,000 entries on sesquiterpenes, of which almost 5,000 contain at least one lactone group.

1.1 Structural Subtypes of Sesquiterpene Lactones

Sesquiterpene lactones are built on a 15-carbon (three isoprene unit) skeleton. Five major STL types — germacranolides, guaianolides, eudesmanolides, heliangolides, and pseudoguaianolides — and three minor STL types (elemanolides, eremophilanolides, and xanthanolides), as well as artemisinin, are represented by structural backbones and specific examples together with plant species where the molecules are found.

A key structural feature underlying the biological reactivity of many STLs is the α-methylene-γ-butyrolactone moiety. The α-methylene-γ-butyrolactones are part of a large and varied group of bioactive natural products widely present in plants. Their high chemical reactivity arises because of an α,β-unsaturated carbonyl system which allows the formation of covalent adducts with nucleophilic residues on diverse biomolecules. Most of these chemicals are of the sesquiterpene type (15-carbon-atom molecule) with an α-methylene group directed exocyclically to the γ-lactone ring. They are classified into 6 main groups of sesquiterpene lactone (SQL) structures: guaianolide, pseudoguaianolide, xanthonolide, eremophilanolide, eudesmanolide, and germacranolide. They are the predominant allergens in the Compositae family as well as in other related plant families such as Jubulaceae, Magnoliaceae, Winteraceae, and Lauraceae.

2. Natural Sources and Botanical Occurrence

Sesquiterpene lactones (SL), characterized by their high prevalence in the Asteraceae family, are one of the major groups of secondary metabolites found in plants. The Asteraceae (daisy/composite) family — which includes feverfew, artichoke, chicory, chamomile, dandelion, arnica, mugwort, yarrow, sunflower, and wormwood — is the single most important source family of medicinal sesquiterpene lactones.

Lactone rings occur widely as building blocks in nature, such as in ascorbic acid, kavain, nepetalactone, gluconolactone, hormones (spironolactone, mevalonolactone), enzymes (lactonase), neurotransmitters (butyrolactone, avermectins), antibiotics (macrolides like erythromycin; amphotericin B), anticancer drugs (vernolepin, epothilones), phytoestrogens (resorcylic acid lactones, cardiac glycosides).

Key medicinally important botanical sources of natural lactones include:

Tanacetum parthenium (Feverfew): Principal source of parthenolide, a germacranolide-type sesquiterpene lactone. Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development.
Artemisia annua (Sweet wormwood): Artemisinin is an antimalarial drug derived from the sweet wormwood plant, Artemisia annua. Artemisinin is a sesquiterpene lactone (a compound made up of three isoprene units bound to cyclic organic esters) and is distilled from the dried leaves or flower clusters of A. annua.
Andrographis paniculata (Kalmegh / King of Bitters): Andrographolide is an extremely bitter C20 labdane diterpenoid, first isolated by Chakravarti and Chakravarti in 1951 from the stem and leaves of Andrographis paniculata (Burm.f.) Nees. It is sparingly soluble in water with a density of 1.2317 g/cm³ and has the molecular formula C₂₀H₃₀O₅.
Cynara scolymus (Globe artichoke): Source of cynaropicrin, a guaianolide-type STL. Cynaropicrin (Cyn), a major component of common artichoke Cynara scolimus L., has shown a wide range of pharmacological properties, such as antihyperlipidemic, anti-trypanosomal, antimalarial, antispasmodic and antiphotoaging, as well as anti-inflammatory activity, associated with the suppression of the key proinflammatory NF-κB pathway.
Arnica montana: Source of helenalin, a pseudoguaianolide-type STL. Helenalin is a sesquiterpene lactone from Arnica montana that mediates by impeding NF-κB and p65 and anomalous stimulation of the NF-κB pathway.
Inula helenium (Elecampane): Source of alantolactone and isoalantolactone, eudesmanolide-type STLs.
Dairy products: Dairy products are typically rich in gamma-lactones, 10- and 12-carbon atoms.
Oak wood: Lactones are present in oak wood, and they contribute to the flavour profile of barrel-aged beers.

Beyond plants, because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Several are produced microbially: another valuable lactone, sclareolide, can be derived from clary sage sclareol in a microbial biotransformation using Cryptococcus albidus, Bensingtonia ciliata, or Cryptococcus laurentii.

3. Traditional and Historical Use

3.1 Artemisia annua and Artemisinin — East Asian Tradition

The antipyretic (fever-reducing) properties of the plant were first recognized in the 4th century CE by Chinese physicians, who called the plant qinghao and recommended a natural remedy in the form of qinghao tea. In the following centuries, this remedy was commonly prescribed for hemorrhoids and malaria. The active agent, called qinghaosu, was isolated from the plant in the 1970s; this compound became widely known as artemisinin. The history of the modern rediscovery is notable: Mao Tse-tung himself answered the Vietnamese call for antimalarial assistance and launched the 523 research programme (named after its official starting date, 23rd of May 1967), which not only led to the discovery of artemisinin but also new quinoleine derivatives that are now used as partner molecules to what is known as "Artemisinin based Combination Therapy" or ACT.

Artemisinin is an unusual sesquiterpene lactone endoperoxide that has been isolated as the active principle of the Chinese antimalarial herb Artemisia annua L. Medicinal herbs from traditional Chinese medicine, such as Artemisia genus, hold a unique position since this enormous variety of drugs of plant origin is founded on more than 5,000 years of tradition.

3.2 Andrographis paniculata — South and Southeast Asian Tradition

Andrographis paniculata (AP), a prominent medicinal plant in Asia, has been traditionally used to treat various ailments, including fever, cough, infections, and inflammation. Its bioactive constituents, particularly the diterpenoid lactones andrographolide (AG), neoandrographolide, 14-deoxyandrographolide, and 14-deoxy-11,12-didehydroandrographolide, alongside other phytochemicals such as flavonoids and phytosterols, have been identified and studied for their anti-inflammatory, antiviral, and immunomodulatory properties.

3.3 Feverfew — European Tradition

Feverfew (Tanacetum parthenium L.) extract is a herbal remedy which has been used for preventing attacks of migraine. The anti-inflammatory sesquiterpene lactone parthenolide is derived from the European traditional herb-medicine feverfew and many Mexican Indian medicinal plants.

3.4 Folk Medicine Uses Across Cultures

Studies of folk medicines implicate sesquiterpene lactones as the active ingredient in many treatments for other ailments such as diarrhea, burns, influenza, and neurodegradation. Sesquiterpenoids, and specifically sesquiterpene lactones from Asteraceae, may play a highly significant role in human health, both as part of a balanced diet and as pharmaceutical agents, due to their potential for the treatment of cardiovascular disease and cancer.

Traditional or folk medicine relies heavily on the use of compounds-rich plants, like those of the Asteraceae family, of which many such species are commercially available in the form of herbal preparations.

4. Key Constituents and Active Compounds

The term "lactones" as used in dietary supplement and natural product contexts most commonly refers to a group of structurally related but chemically distinct molecules. The principal medicinally studied lactone-bearing natural compounds include:

4.1 Parthenolide

The primary active sesquiterpene lactone of feverfew (Tanacetum parthenium). It is a germacranolide with an α-methylene-γ-lactone and an epoxide group. In the flowers of feverfew, the content of the responsible contact allergen parthenolide — a potent sesquiterpene lactone — appeared to be 0.6–0.9%.

4.2 Artemisinin

Artemisinin is a natural bioactive sesquiterpene lactone containing an unusual endoperoxide 1,2,4-trioxane ring. This crystalline compound, called qinghaosu, also referred to as QHS or artemisinin, is a sesquiterpene lactone with an internal peroxide linkage.

4.3 Andrographolide

Andrographolide is a diterpenoid lactone consisting of an α-alkylidene γ-butyrolactone moiety, three hydroxyls at C-3, C-14, and C-19, together with two olefin bonds at Δ12,13 and Δ8,17. It is a diterpene lactone compound with the chemical formula C₂₀H₃₀O₅. Previous research has confirmed that andrographolide has antipyretic and analgesic, anti-inflammatory, antibacterial, antiviral, immune regulatory, anti-tumor, neuroprotective, hepatoprotective, gallbladder protective, and anti-cardiovascular activities.

4.4 Alantolactone and Isoalantolactone

Eudesmanolide-type sesquiterpene lactones isolated from Inula helenium (elecampane). Isoalantolactone (IATL) is an eudesmane-type sesquiterpene lactone isolated from Inula helenium. IATL inhibited cell proliferation with IC₅₀ values in the PC-3, DU-145, and LNCaP cell lines of 27.84 ± 3.34, 33.84 ± 4.06, and 29.84 ± 3.76 μM, respectively. IATL caused reactive oxygen species-dependent apoptosis in prostate cancer cells by inhibiting survivin.

4.5 Helenalin

A pseudoguaianolide-type STL from Arnica montana. Helenalin inhibits essential factors in both cancer and inflammation, i.e., the NF-κB pathway and the transcription of inflammatory cytokines. Helenalin causes sub-G1 halt, caspase cleavage, apoptosis, and a rise in autophagic marker concentrations.

4.6 Cynaropicrin

A guaianolide-type STL from globe artichoke (Cynara scolymus). Antitrypanosomal, antitumor, and anti-inflammatory activities are reported for cynaropicrin. Studies have established that cynaropicrin interrupts the thioredoxin (Trx) system via thioredoxin reductase (TrxR) inhibition, leading to oxidation of Trx and accumulation of ROS in HeLa cells. Principally, cynaropicrin cytotoxicity is increased via the genetic knockdown of TrxR, depicting that the pharmacological outcome of cynaropicrin is associated with TrxR inhibition.

4.7 γ-Butyrolactone Scaffold Compounds

Several γ-butyrolactone-containing drugs have been FDA-approved and used in clinic for diverse purposes such as diuretics, anticancer agents, contraceptive drugs, treatment of heart disease, and anti-glaucoma agents. γ-Lactones are present in the structure of several natural products, such as the γ-saturated butyrolactone and the α-β-unsaturated butenolides.

4.8 Andrographis-Derived Diterpene Lactone Congeners

The bioactive constituents of Andrographis paniculata include particularly the diterpenoid lactones andrographolide (AG), neoandrographolide, 14-deoxyandrographolide, and 14-deoxy-11,12-didehydroandrographolide, alongside other phytochemicals such as flavonoids and phytosterols, which have been identified and studied for their anti-inflammatory, antiviral, and immunomodulatory properties.

5. Established Mechanisms of Action

5.1 NF-κB Pathway Inhibition

The inhibition of nuclear factor kappa-B (NF-κB) is the best-characterized mechanism by which sesquiterpene lactones exert anti-inflammatory and anti-tumor effects. The transcription factor NF-κB is a key regulator of the cellular inflammatory and immune response. Therefore, components of the NF-κB-activating signaling pathways are frequent targets for anti-inflammatory agents. The sesquiterpene lactone parthenolide inhibits a common step in NF-κB activation by preventing the TNF-α-induced induction of IκB kinase (IKK) and IKK-β, without affecting the activation of p38 and c-Jun N-terminal kinase.

Evidence shows that parthenolide uses a similar mechanism to other SLs in inhibiting NF-κB. Contrary to previous reports, parthenolide, like other SLs, inhibits NF-κB most probably by alkylating p65 at Cys38. SLs interfere with cellular processes including oxidative phosphorylation, platelet aggregation, and histamine and serotonin release, as well as neutrophil chemotaxis. In previous studies, SLs selectively inhibit DNA binding of the transcription factor NF-κB.

For andrographolide: The molecular and cellular mechanisms responsible for the immunomodulating and anti-inflammatory properties of andrographolide indicate that andrographolide inhibits NF-κB. Specifically, andrographolide in concentrations of 10 μM interferes with the DNA binding of NF-κB, reducing the expression of COX-2 in neutrophils induced with fMLP and PAF.

5.2 Inhibition of Prostaglandin Synthesis and Lipoxygenase Pathways

Parthenolide inhibits prostaglandin synthetase in vitro and seems to possess analgesic properties. The broader class of sesquiterpene lactones has been shown to inhibit both cyclooxygenase and lipoxygenase pathways. Sesquiterpene lactone mechanisms of action have been investigated extensively, and some of their reported molecular targets include acid phosphatase, aryl sulfatase, cathepsins, cyclooxygenase, DNA, DNA polymerase, glycogen synthase, 5-lipoxygenase, phosphofructokinase, and phospholipase A2.

5.3 Alkylation of Cysteine Residues

The α,β-unsaturated carbonyl system of the lactone ring is a central feature enabling biological activity. As reported for many SLs, the nucleophilic α,β-unsaturated carbonyl group of the lactone ring is able to form covalent bonds with sulfhydryl groups of several biomolecules via a Michael addition. This mechanism underlies both the therapeutic effects and the allergenic potential of STLs.

5.4 Pro-apoptotic and Anti-tumor Mechanisms

Parthenolide's molecular events and cell-specific activities include interactions with cytochrome c, NF-κB, STAT, reactive oxygen species (ROS), TCP, HDACs, microtubules, and inflammasomes. Parthenolide shows strong NF-κB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes. This compound acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-β). Similarly, parthenolide-induced ROS-mediated apoptosis of tumor cells occurs via the intrinsic apoptotic signaling pathway.

In addition to the anti-inflammatory response, sesquiterpene lactones have been found to sensitize tumor cells to conventional drug treatments.

5.5 Endoperoxide Activity of Artemisinin

This unusual sesquiterpene lactone possesses an endoperoxide moiety and is a component of the Chinese antimalarial drug Qinghaosu. It has been successful in treating cases of chloroquine-resistant Plasmodium falciparum and particularly cerebral malaria.

5.6 Immunomodulatory Effects

Andrographolide reduces the production of IFNγ and IL-2 in T cells stimulated with Con-A, without affecting the cellular viability or inducing apoptosis. Also, the apoptosis induced by corticosteroids in thymocytes was reduced. Andrographolide and 14-deoxyandrographolide are able to inhibit ERK1/2 phosphorylation in T cells and neutrophils, respectively.

5.7 Ecological Roles That Inform Bioactivity

STLs play roles in plant defence mechanisms against herbivory and as phytotoxins, alongside their function as environmental signalling molecules. Some sesquiterpenoid lactones are antimicrobial, disrupting the cell wall of fungi and invasive bacteria, whereas others protect the plant from environmental stresses that would otherwise cause oxidative damage. Many of the compounds are effective due to their bitter flavor, which has obvious implications for human consumers.

6. Scientific Evidence by Area of Use

6.1 Migraine Prevention (Feverfew / Parthenolide)

Evidence level: Mixed to moderate; low-quality by Cochrane assessment.

Feverfew (Tanacetum parthenium L.) extract is a herbal remedy which has been used for preventing attacks of migraine. The systematic review assessed evidence from double-blind randomised controlled trials (RCTs) evaluating the clinical efficacy and safety of feverfew monopreparations versus placebo for preventing migraine.

A 2025 updated systematic review and meta-analysis is currently the most comprehensive assessment: A comprehensive search of PubMed, EMBASE, and Google Scholar up to August 2025 identified nine double-masked, placebo-controlled RCTs involving 899 participants. Feverfew significantly reduced migraine attack frequency (IV: −1.11 [−1.23 to −0.99], p < 0.00001; I² = 28%) and migraine duration (IV: −4.43 [−7.63, −1.23] at 95% CI, p = 0.007; I² = 98%), and showed a non-significant trend towards reduced pain severity. No significant effects were observed on migraine associated symptoms such as nausea, vomiting, photophobia, and phonophobia.

The Cochrane review (Wider et al., 2015) noted: Since the last version of this review, one larger rigorous study has been included, reporting a difference in effect between feverfew and placebo of 0.6 attacks per month. This adds some positive evidence to the mixed and inconclusive findings of the previous review. However, this constitutes low quality evidence, which needs to be confirmed in larger rigorous trials with stable feverfew extracts and clearly defined migraine populations before firm conclusions can be drawn.

Persistent methodological concerns include standardization: Clinical trials of feverfew for the prevention of migraine attacks published in the 1980s and 1990s produced inconsistent results; wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations were suggested as explanations. There was a variability in the formulations of feverfew used in these studies, including freeze-dried powder, parthenolide-specific formulations, and CO₂-extracts. There was an inconsistency in the preparation and a lack of standardization in the key active compound, parthenolide concentration, which contributed to variable findings.

The modality of data collection and reporting in the individual studies does not support a pooling of results, but does suggest benefit of feverfew in migraine prophylaxis for at least subsets of the population with the disorder. Pharmacologically, there is some potential for concern with long-term dosing given its cyclooxygenase-2 inhibiting effects, and longer-term studies will be needed to ameliorate these concerns in coronary disease patients.

6.2 Antimalarial Activity (Artemisinin)

Evidence level: Robust — WHO-recommended pharmaceutical; extensive clinical trial data.

Artemisinin is an unusual sesquiterpene lactone (SL) endoperoxide that has been isolated as the active principle of the Chinese antimalarial herb Artemisia annua L. Since artemisinin was discovered to be the active component of A. annua in the early 1970s, hundreds of papers have focused on the antiparasitic effects of artemisinin and its semi-synthetic analogues. Nowadays, artemisinin and its derivatives have become essential components of antimalarial treatment and are recommended by the World Health Organization (WHO) to treat especially multidrug-resistant forms of malaria.

Historical clinical evidence: Artemisinin or QHS was the subject of a 1979 study conducted by the Qinghaosu Antimalarial Coordinating Research Group involving the treatment of 2,099 cases of malaria (Plasmodium vivax and Plasmodium falciparum in a ratio of about 3:1) with different dosage forms of QHS, leading to the clinical cure of all patients. Artemisinin was found to be highly effective at suppressing the parasitemias caused by P. falciparum and P. vivax, including those caused by multidrug-resistant Plasmodium strains insensitive to conventional antimalarial drugs such as chloroquine and sulfadoxine-pyrimethamine. In addition, artemisinin exhibits several other advantageous features as an antimalarial agent such as rapid onset of action, high therapeutic index, and high activity against all of the blood stages of parasite infection, inducing 10- to 100-fold higher reduction in parasitemia per cycle compared to other antimalarial agents.

6.3 Anti-Inflammatory and Immunomodulatory Applications

Evidence level: Strong mechanistic and preclinical; limited but growing human clinical data for individual compounds.

The overarching NF-κB inhibition mechanism is well-established across multiple in vitro and in vivo studies. With new SLs discovered in recent years, new biological activities have been tested, including different action mechanisms (synergistic and/or antagonistic effects), as well as molecular structure-activity relationships. The review identifies the main sesquiterpene lactones with interconnections between immune responses and anti-inflammatory actions, within different cellular models as well as in in vivo studies.

For andrographolide in particular: Andrographolide is a naturally derived bioactive compound with promising anti-inflammatory activity in many clinical studies. Studies on andrographolide for treating inflammatory diseases have been increasing and it is widely used in China to treat inflammatory diseases and autoimmune diseases, including chronic obstructive pulmonary disease. By reviewing the application and mechanism of andrographolide in the treatment of inflammatory diseases, it has been found that andrographolide has good anti-inflammatory and immunomodulatory effects and is a promising drug for inflammatory diseases.

Clinically derived preparations: Clinically, derivative agents such as Lianbizhi injection, Chuanhuning, Yanhuning injection, and Xiyanping injection can be used in the treatment of bronchitis, tonsillitis, pneumonia, etc.

Early in vitro evidence establishing the NF-κB mechanism: The ethanolic leaf extracts of Artemisia ludoviciana ssp. mexicana, Calea zacatechichi, and Polymnia maculata (all rich in sesquiterpene lactones) were identified as inhibitors of NF-κB down to a concentration of 25 μg/ml. The sesquiterpene lactones isohelenin and parthenolide prevented NF-κB activation completely as low as 5 μM.

6.4 Anticancer Research

Evidence level: Predominantly preclinical (in vitro and animal); very limited human clinical trial data for most individual lactones.

Plants-based natural compounds are well-identified and recognized chemoprotective agents that can be used for primary and secondary cancer prevention, as they have proven efficacy and fewer side effects. In today's scenario, when cancer cases rapidly increase in developed and developing countries, anti-cancerous plant-based compounds become highly imperative.

Sesquiterpene lactones and their derivatives are now used worldwide to create and manufacture innovative cancer therapeutics. The most prominent sesquiterpene lactones identified were artemisinin, alantolactone, costunolide, helenalin, cynaropicrin, parthenolide, and inuviscolide, which are originated from botanical sources like Ferula penninervis, Tanacetum argenteum, Artemisia kopetdaghensis, Cichorium intybus, Carpesium divaricatum, and Leptocarpha rivularis.

In addition to the anti-inflammatory response, sesquiterpene lactones have been found to sensitize tumor cells to conventional drug treatments. Alantolactone was shown in vivo to be able to reduce tumor size by over 50%, while increasing life expectancy and reducing pathological indicators across several different cancer types. In addition, synergistic effects with well-known cancer therapeutics were also reported. Arglabin in salt form could be used to treat several cancers and possesses valuable pharmacokinetic characteristics highly sought for in therapeutic drugs.

For cancer applications: Among 1,703 identified literature articles on andrographolide's cytotoxic/anticancer effects, 139 were included in a systematic review; 109 were investigated as non-clinical, whereas 24, 3, and 3 were pre-clinical, clinical, and non-pre-clinical trials, respectively. This underscores that human clinical evidence for most lactone-based anticancer applications remains sparse compared to the extensive in vitro and animal literature.

The safety, efficacy, and bioactivity of sesquiterpene lactones must be evaluated via clinical trials, in vitro studies, and in vivo research.

6.5 Rheumatoid Arthritis and Skeletal Disease

Evidence level: Preliminary; mostly preclinical. One noted clinical trial for andrographolide in RA.

The diterpene lactone andrographolide, isolated from Andrographis paniculata, has been proven to possess several important protective biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiseptic, antimicrobial, cytotoxic, hypolipidemic, cardioprotective, hepatoprotective, and neuroprotective effects. In addition, it has been reported to play a therapeutic role in the treatment of major human diseases, such as Parkinson's disease, rheumatoid arthritis, and colitis.

Parthenolide was found to block lipopolysaccharide (LPS)-induced osteolysis via the inhibition of osteoclast formation and bone resorption. Mechanically, parthenolide was found to inhibit NF-κB activity induced by pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and receptor activator of nuclear factor kappa-B ligand (RANKL), all of which have an inductive effect on osteoclast formation and activation.

Observational data suggest feverfew may also alleviate headaches in pediatric cases, but it had no benefits in patients with rheumatoid arthritis.

6.6 Cardiovascular and Metabolic Effects

Evidence level: Preclinical and early clinical.

Pretreatment with andrographolide, but not with other compounds from A. paniculata, protected cardiomyocytes against hypoxia/reoxygenation injury and up-regulated the cellular-reduced glutathione (GSH) level and antioxidant enzyme activities. The cardioprotective action of andrographolide was found to coincide in a time-dependent manner with the up-regulation of GSH, indicating the important role of GSH.

6.7 Respiratory and Infectious Disease

Evidence level: Clinical data for Andrographis preparations; active research area.

Andrographolide has the effect of treating respiratory, digestive immune, cardiovascular, and nervous system diseases. Virus-based diseases like ZIKA, influenza A virus subtype (H1N1), Ebola (EBOV), Dengue (DENV), and coronavirus (COVID-19) epidemics have greatly increased scientific interest and demands to develop more effective and economical immunomodulating drugs with minimal side effects.

7. Body Systems and Health Areas Associated with Lactones

Immune system: NF-κB modulation, cytokine regulation, T-cell activity, macrophage activation.
Nervous system: Migraine prevention (feverfew/parthenolide); neuroprotection (andrographolide); bitter receptor stimulation.
Cardiovascular system: Cardioprotective activity (andrographolide); antiplatelet effects (parthenolide); hypolipidemic effects.
Digestive system: Choleretic, hepatoprotective, and anti-ulcer effects; antiparasitic activity in the gut.
Musculoskeletal system: Inhibition of osteoclast-mediated bone resorption; anti-arthritic effects.
Infectious disease: Antimalarial (artemisinin); antiviral; antibacterial; antifungal.
Oncology: Apoptosis induction, sensitization of tumor cells to chemotherapy, NF-κB-dependent transcriptional suppression.
Skin: Anti-inflammatory and antiallergic (relevant also to contact sensitization).

Sesquiterpenoids, and specifically sesquiterpene lactones from Asteraceae, may play a highly significant role in human health, both as part of a balanced diet and as pharmaceutical agents, due to their potential for the treatment of cardiovascular disease and cancer.

8. Dosage Forms and Doses Reported in Studies

Lactone-bearing supplements are available in diverse forms. The percentage of diterpenes in various dosage forms, including capsules, liquids, tea bags, and powder, has been studied across different Andrographis paniculata-containing dietary supplements.

Substantial variation in the percentage of andrographolide and the sum of diterpene lactones has been observed across different Andrographis-containing dietary supplements. The developed chromatographic method was applied across botanical samples and dietary supplements claiming to contain only A. paniculata to assess their content against various pharmacopeias such as USP, EP, IP, and TP, and to identify the supplements having substandard quality in terms of diterpene lactones content.

For feverfew in migraine trials: The small sample size in the clinical trials, ranging from 17 to 170 participants, limits the statistical power to detect subtle treatment effects. Formulations evaluated across trials included freeze-dried leaf powder, ethanolic extracts, and CO₂ extracts, with parthenolide content varying widely between preparations.

For NF-κB inhibition mechanistic studies: The sesquiterpene lactones isohelenin and parthenolide prevented NF-κB activation completely as low as 5 μM. For andrographolide: Andrographolide in concentrations of 10 μM interferes with the DNA binding of NF-κB, reducing the expression of COX-2 in neutrophils induced with fMLP and PAF. These are in vitro concentrations and do not directly translate to supplement dosing.

For cynaropicrin in glioblastoma cells: Cyn at 4, 8, and 10 μM displayed significant cytotoxicity, as confirmed by the cell count and MTT assay. Again, these are laboratory concentrations used in cell-based experiments.

By implementing alterations to the chemical structure, scientists have successfully created a range of andrographolide derivatives that exhibit enhanced bioavailability, good in vitro and in vivo anti-inflammatory activity, and safety profiles.

9. Safety Considerations and Interactions

9.1 Allergic Contact Dermatitis and Compositae Allergy

Sesquiterpene lactones are a large, diverse group of chemicals found in several plant families that cause allergic contact dermatitis. This is the most established and clinically significant adverse effect of sesquiterpene lactone-containing plants and preparations.

The baseline series of patch test allergens usually contains sesquiterpene lactone mix (alantolactone, dehydroxosus lactone, costunolide), and may also contain compositae mix. Related plant allergens include parthenolide and specific extracts prepared from individual plants such as dandelion, tansy, yarrow, feverfew, chamomile, arnica, and chrysanthemum. In one study, sesquiterpene mix detected 65% and compositae mix detected 87% of compositae-allergic patients. Parthenolide detects 75% of sesquiterpene lactone-allergic patients.

A case of specific, delayed hypersensitivity induced by repeated contact with a wild form of feverfew (Tanacetum parthenium) has been reported. In the flowers investigated, the content of the responsible contact allergen parthenolide — a potent sesquiterpene lactone — appeared to be 10 times greater (0.6–0.9%) than in earlier years. Cross-reactions were elicited with 11 of 21 mostly Compositae plants containing chemically related sesquiterpene lactones. The strongest reactions were elicited by tansy, yarrow (milfoil), marguerite, aster, sunflower, laurel, and Frullania.

9.2 Systemic Allergic Dermatitis

Patients with Compositae sensitization are routinely warned against the ingestion of vegetables, spices, teas, and herbal remedies from this family of plants. The evidence for the occurrence of systemic allergic dermatitis caused by sesquiterpene lactone-containing plants is mostly anecdotal and based on statements from patients rather than scientific data. However, a few clinical reports on accidental sensitization and exposure and oral challenge prove the existence of this kind of reaction, most convincingly for strong contact allergens such as costunolide in bay leaves, and less so for weak allergens such as those of lettuce.

Other Compositae species suspected of causing systemic reactions are artichoke, mugwort, yarrow, dandelion, feverfew, and elecampane. Some Compositae vegetables and teas, such as lettuce and chamomile tea, may induce systemic reactions through both humoral and cell-mediated mechanisms.

9.3 Oral Mucosal Reactions

If the leaves of the plant are chewed, the lips, tongue, and mouth may become inflamed and mouth ulcers may occur.

9.4 Photosensitivity

It is believed that chronic contact allergic dermatitis to Compositae slowly evolves to photocontact dermatitis and then to photosensitivity even in the absence of known contact with Compositae. These patients are exquisitely sensitive to ultraviolet radiation so that dermatitis appears on skin exposed to sunlight for just a few minutes. It is thought that about 20–75% of patients with compositae dermatitis have some degree of photosensitivity.

9.5 Toxicological Properties and Alkylating Potential

Sesquiterpene lactones (STLs) present a wide range of biological activities, mostly based on their alkylating capabilities, which underlie their therapeutic potential. These compounds are the active constituents of a variety of plants, frequently used as herbal remedies. STLs such as artemisinin and its derivatives are in use as first-line antimalarials while others, such as parthenolide, have recently reached cancer clinical trials. However, the toxicological profile of these compounds must be thoroughly characterized, since the same properties that make STL useful medicines can also cause severe toxicity.

9.6 Cyclooxygenase Inhibition and Cardiovascular Concern

Pharmacologically, there is some potential for concern with long-term dosing given its cyclooxygenase-2 inhibiting effects, and longer-term studies will be needed to ameliorate these concerns in coronary disease patients.

9.7 Quality and Standardization Issues

The lack of standardization across commercial preparations is a documented safety and efficacy concern. Wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations have been suggested as explanations for inconsistent clinical results. Substantial variation in the percentage of andrographolide and the sum of diterpene lactones has been observed across different Andrographis-containing dietary supplements.

9.8 Overall Safety Profile of Feverfew

It appears from the data reviewed that feverfew is not associated with any major safety concerns. This refers to the overall safety profile at doses studied in migraine prevention trials, distinct from the contact sensitization risk discussed above.

10. Regulatory and Research Context

Sesquiterpene lactones, a vast range of terpenoids isolated from Asteraceae species, exhibit a broad spectrum of biological effects and several of them are already commercially available, such as artemisinin. In the authors' opinion, many sesquiterpene lactones have been neglected compared to others, although they could be of great use in developing important new pharmaceutical products. The selected sesquiterpenes show promising anticancer and anti-inflammatory effects, acting on various targets. Moreover, they exhibit antifungal, anxiolytic, analgesic, and antitrypanosomal activities.

Several studies clearly show the potential that some sesquiterpene lactones have in combination therapy, as sensitizing agents to facilitate and enhance the action of drugs in clinical use. The derivatives show greater pharmacological value since they have better pharmacokinetics, stability, potency, and/or selectivity. All these natural terpenoids and their derivatives exhibit properties that invite further research by the scientific community.

Researchers from distinct research fields, including pharmacology, medicine, and agriculture, are interested in the biological potential of sesquiterpene lactones. The field represents an active area of pharmaceutical research, with derivative synthesis, improved delivery systems, and combination therapy studies all under active investigation.

References

Health Conditions

Health conditions that Lactones may help support.

No conditions available.

Body Systems

Body systems that Lactones may help support.

No body systems available.