IngredientsDiterpenoids comprise a varied group of secondary metabolites that are isoprene-derived compounds consisting of four isoprene units. More precisely, diterpenes are a specific subclass defined by their chemical structure as C20 molecules, constructed from four isoprene units, with a fundamental architecture formally derived from the head-to-tail assembly of these units, and the linear precursor molecule for all diterpenes in nature is geranylgeranyl pyrophosphate (GGPP).
The diterpenoids are a large and ubiquitous family of isoprenoids derived from 2E,6E,10E-geranylgeranyl pyrophosphate. Enzymes known as diterpene synthases then act on this precursor to fold the carbon chain into various shapes, giving rise to an extraordinary structural diversity. Diterpenes are one of the classes of natural products with about 7000 known structures.
Diterpenoid natural products cover a vast chemical diversity and include many medicinally and industrially relevant compounds. All diterpenoids derive from a common substrate, (E,E,E)-geranylgeranyl diphosphate, which is cyclized into one of many scaffolds by a diterpene synthase (DTS).
Diterpenes are classified mainly according to their chemical structure, in terms of the ring number they contain, as: acyclic (phytane), monocyclic (retinol—vitamin A), bicyclic (labdane, halimane, clerodane), tricyclic (abietane, pimarane, cassane, rosane, podocarpane, chinane, vouacapane), tetracyclic (kaurane, trachylobane, aphidicolane, stemodane, stemarane, beyerane, atisane, scopadulane, gibberellane), and macrocyclic (polycyclic—cembrane, taxane, daphnane, tigliane, ingenane, jatrophane), and other miscellaneous structures.
The labdane-related diterpenoids are a special group, consisting of over 7,000 members, which are distinguished by their unique biosynthesis. Among the most pharmacologically and industrially important structural classes are the taxanes (e.g., paclitaxel from yew trees), kauranes (e.g., gibberellins, steviol), labdanes (e.g., andrographolide, forskolin), abietanes (e.g., tanshinone IIA from Salvia miltiorrhiza), and clerodanes. Diterpenes (C20H32) include taxadiene from yew trees, gibberellins as plant hormones, phytol in chlorophyll, steviol in Stevia leaves, and retinol (Vitamin A1) derived from β-carotene.
Diterpenes, obtained from plants, fungi, insects, microbes and marine organisms, are a complex group of structurally diverse secondary metabolites with a wide spectrum of biological activities. Diterpenes are common compounds naturally exuded from the trunks of the Cistaceae, Leguminoseae, Burseraceae, Lamiaceae and Euphorbiaceae botanical families as an adhesive lipophilic resin.
Key plant families and their characteristic diterpene-producing genera include:
While diterpene biosynthesis has been extensively studied in plants and fungi, bacteria are now recognized for their production of unique diterpenoids and are likely to harbor an underexplored reservoir of new diterpene synthases.
Diterpenes are encountered in a range of commercial and traditional preparations. As a class, they appear in:
Forskolin is a diterpene derived from the root of Coleus forskohlii. It has been used for centuries in Ayurvedic medicine to treat a variety of conditions including heart disease, respiratory disorders, and hypothyroidism. Ancient Hindu Ayurvedic texts described the use of extracts from Coleus species. Coleus forskohlii is a south Asian herb that has been historically used in Ayurvedic medicine.
Tanshinone IIA (Tan IIA) is widely used in the treatment of cardiovascular diseases as an active component of Salvia miltiorrhiza Bunge. The plant, known as Danshen, is used in TCM for promoting blood circulation, regulating menstruation, removing blood stasis, relieving pain, cooling blood, eliminating carbuncle, and tranquilization.
Tripterygium wilfordii Hook F (TWHF) is used as a traditional Chinese medicine, called thunder god vine, based on its efficacy for treating inflammatory diseases. The extracts of TWHF containing triptolide have been used for the therapy of inflammation and autoimmune diseases including rheumatoid arthritis, immune complex nephritis and systemic lupus erythematosus.
Andrographolide, from Andrographis paniculata (known as "Chuan Xin Lian" in Chinese), has long been used in Chinese herbal medicine for its bitter, cooling properties in treating infections and fever. Andrographolide is a diterpene lactone compound in the Chinese medicine Andrographis paniculata Nees.
Andrographis paniculata (Burm. f.) Nees, an annual herb from the family Acanthaceae and cultivated in southern Asia, is a source of diterpenes used extensively in traditional Indian, Thai, and other Southeast Asian medicine systems for upper respiratory infections, fever, and digestive complaints.
Rosemary's culinary and medicinal uses date back to ancient civilizations, where it was revered for its therapeutic properties. Throughout history, rosemary has been utilized for various purposes, including flavoring food, producing fragrances, and treating a wide range of ailments. In traditional medicine, rosemary has been employed as an antispasmodic agent for treating renal colic and dysmenorrhea, alleviating respiratory conditions, and promoting hair growth. Among the most notable bioactive constituents of rosemary are the diterpenes carnosic acid and carnosol.
Diterpene, a type of terpene, is one of the outstanding chemical structures inside propolis and has shown a broad array of biological effects, such as antibacterial, antioxidant, anti-inflammatory, antifungal, antiplatelet, anticancer, and antihypertensive activities.
Of all the families of natural products, the diterpenoids have one of the widest ranges of biological activity. Diterpenes, or diterpenoids, are the most abundant and diverse subgroup of terpenoids, the largest family of secondary metabolites. Most diterpenes possess broad biological activities including anti-inflammatory, antiviral, anti-tumoral, antimicrobial, anticancer, antifungal, antidiabetic, cardiovascular protective, and phytohormone activities.
Source: Andrographis paniculata
Andrographolide is a bicyclic diterpenoid lactone and main bioactive chemical constituent of this plant with remarkable antitumor activity. Other diterpenes structurally analogous to andrographolide are also present in the extract of Andrographis paniculata, such as neoandrographolide, homoandrographolide, and isoandrographolide.
Mechanistically, andrographolide exerts anti-inflammatory effects by suppressing NF-κB signaling, inhibiting pro-inflammatory cytokines, and modulating immune responses. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways. These substances could reduce arthritis score, downregulate oxidative, proinflammatory, and inflammatory biomarkers, modulate various arthritis pathways, and improve joint destruction and clinical arthritic conditions, signs, symptoms, and physical functions.
Source: Taxus brevifolia and related yew species
PTX (marketed as Taxol®) is a tetracyclic diterpenoid that was initially discovered in the bark of Taxus brevifolia, a Pacific yew tree. The antitumor activity of paclitaxel is due to a promotion of microtubule polymerization, stabilizing microtubules and preventing their depolymerization — thereby blocking cell division.
Source: Salvia miltiorrhiza (Danshen)
Bioactive chemical constituents from Salvia miltiorrhiza are classified into two categories: lipophilic diterpene quinones and water-soluble phenolic acids. Tanshinone IIA (Tan IIA) is one of the lipophilic constituents. TanIIA suppresses tissue inflammation and fibrosis through signaling pathways such as PI3K/Akt/mTOR/eNOS, TGF-β1/Smad2/3, NF-κB, JNK/SAPK (stress-activated protein kinase)/MAPK, and ERK/Nrf2 pathways. The therapeutic efficacy is mediated through multiple mechanisms, including anti-atherosclerotic effects, lipid homeostasis regulation, anti-arrhythmic properties, myocardial functional enhancement, and hemodynamic stabilization.
Source: Coleus forskohlii (syn. Plectranthus barbatus)
Forskolin (chemical formula C22H34O7) directly activates adenylate cyclase to raise intracellular cAMP and modulate lipolysis, smooth-muscle tone, and platelet function. In animal models, forskolin promoted activation of adenylate cyclase and increased intracellular concentrations of cyclic adenosine monophosphate (cAMP). Forskolin is a labdane diterpenoid with antihypertensive, positive inotropic, platelet aggregation inhibitory, and adenylate cyclase activating properties. In isolated heart tissue, forskolin activates a membrane-bound adenylate cyclase and a cytoplasmic cAMP-dependent protein kinase to a much higher degree than does isoprenaline. This activation does not require the hormone receptor.
Source: Tripterygium wilfordii (Thunder God Vine)
Triptolide (TP) is a diterpene triepoxide, which is the major pharmacologically active ingredient and toxic component of Tripterygium wilfordii. Based on its activities, TP is used as a caspase activator and inhibitor of NF-κB. TP has attracted the attention of researchers because of its high potential for clinical application, such as its anti-inflammatory, anti-cancer, anti-immune, and anti-oxidant effects.
Source: Rosmarinus officinalis / Salvia rosmarinus (Rosemary)
Carnosic acid and carnosol are lipophilic diterpenes that exhibit neuroprotective properties, possibly by modulating Nrf2 pathways involved in cellular defense. Carnosic acid and carnosol are diterpenes that represent about 5% of R. officinalis dried leaves weight, and these compounds have greater antitumor relevance.
Inhibitions of α-glucosidase and protein tyrosine phosphatase 1B (PTP 1B) activities and peroxisome proliferator-activated receptors gamma (PPAR-γ) agonistic property were the most frequently used models for studying the antidiabetic activity of diterpenes. The molecular mechanisms of action of the diterpenes include increased GLUT4 translocation, and activation of phosphoinositide 3-kinase (PI3K) and AMP-activated protein kinase (AMPK)-dependent signaling pathways.
Several diterpenes have been shown to have pronounced cardiovascular effects; for example, grayanotoxin I produces positive inotropic responses, forskolin is a well-known activator of adenylate cyclase, eleganolone and 14-deoxyandrographolide exhibit vasorelaxant properties, and marrubenol inhibits smooth muscle contraction by blocking L-type calcium channels. These diterpenoids exhibit vasorelaxant action and inhibit vascular contractility mainly by blocking extracellular Ca²⁺ influx. Moreover, kaurane and pimarane-type diterpenes decreased mean arterial blood pressure in normotensive rats.
Diterpenes exhibit immunomodulatory effects by influencing the production of cytokines and other signaling molecules involved in the immune response. These actions contribute to achieving a more balanced immune profile. Diterpenoids have a variety of biological functions, including antioxidant, anti-inflammatory, and immune-modulatory action.
Evidence level: Strong (Phase III/IV clinical trials; FDA-approved drug)
PTX (paclitaxel) is the first taxane to undergo clinical trials and is an active chemotherapy drug against a wide range of cancers, typically resistant to conventional treatments. The US FDA in 1992 approved it for ovarian cancer treatment, and for advanced and early-stage breast cancer treatments in 1994 and 1999, respectively. PTX is administered as a second-line drug in monotherapy when combination chemotherapy fails to treat breast cancer or the disease recurs within 6 months of adjuvant chemotherapy.
Research on taxane diterpenoids, commonly known as taxoids, has increased over the past 20 years from a small field of natural product chemistry into a nearly $1 billion business. Docetaxel (Taxotere), a semi-synthetic taxane derivative, is also used clinically. Based on published preclinical data, PTX affects various pathways, causing an overall clinical activity that is not solely dependent on its direct cytotoxic effects on cancer cells.
Evidence level: Moderate for upper respiratory tract infections (multiple RCTs, systematic reviews); methodology quality is variable
Andrographis paniculata (AP) is a traditionally used herbaceous plant whose main active constituent is andrographolide. Andrographolide derivative medications and herbal preparations of AP are often used to treat respiratory tract infections. A total of 262 studies were included in a systematic review and meta-analysis, including 125 randomized controlled trials, 23 non-randomized controlled trials, 6 case series, and 108 case reports.
Clinical trials have demonstrated beneficial results regarding respiratory infections, but the methodology used is often of poor quality. A randomized double-blind placebo-controlled trial evaluated the efficacy and safety of Andrographis paniculata extract for the treatment of acute nonspecific upper respiratory tract infections. Studies of acute and subacute toxicity have shown that the LD50 of andrographolide is more than 5 g/kg when administered orally.
In a study of mild COVID-19, herbal capsules significantly reduced the median time to clear the virus (9 days) compared to other treatments (11–13 days). While no pneumonia was observed, one participant in the AP group developed hyperkalemia. The study suggests AP with or without Boesenbergia rotunda might be a potential alternative for mild COVID-19; however, large-scale clinical trials are necessary to confirm efficacy and safety for a broader patient population.
Evidence level: Moderate (multiple RCTs in China, mainly as adjunct to conventional therapy; predominantly in Chinese-language literature)
The in vivo and in vitro studies showed that tanshinone IIA and salvianolate have a wide range of cardiovascular and other pharmacological effects, including antioxidative, anti-inflammatory, endothelial protective, myocardial protective, anticoagulation, vasodilation, and anti-atherosclerosis, as well as significantly helping to reduce proliferation and migration of vascular smooth muscle cells. In addition, some of the clinical studies reported that S. miltiorrhiza preparations in combination with Western medicine were more effective for treatment of various cardiovascular diseases including angina pectoris, myocardial infarction, hypertension, hyperlipidemia, and pulmonary heart diseases.
Clinical evidence has demonstrated that both Tanshinone IIA (Tan IIA) and its water-soluble derivative sodium Tanshinone IIA sulfonate (STS) exhibit significant therapeutic benefits in CVDs. Accumulating evidence from recent investigations has demonstrated that Tan IIA exhibits multi-target pharmacological properties and modulates diverse signaling pathways in cardiovascular protection, positioning it as a promising candidate in natural product-based drug discovery. The majority of formal clinical evidence comes from China, and large-scale, globally registered RCTs outside of China are limited.
Evidence level: Preliminary (animal models, small human studies)
Research into diterpenes has provided insight into their role in the regulation of arterial blood pressure and intraocular pressure (IOP), and the possible mechanisms underlying their biological effects. The rational for the study of the cardiovascular actions of diterpenes is based on the fact that many medicinal plants contain diterpenoids and their cardiovascular activity can most likely be attributed to these compounds.
Two clinical trials found positive effects with intravenous forskolin for heart disease, but overall support for this use is not strong. In addition, oral forms of this herb have not been tested in humans. For glaucoma, studies in humans have conflicting results.
Evidence level: Preliminary (small RCTs, limited sample sizes)
A randomized, double-blind placebo-controlled clinical study assessed the effects of supplementation with C. forskohlii extract on key markers of obesity and metabolic parameters in overweight and obese individuals. Thirty participants completed the trial and were randomly assigned to receive either 250 mg of C. forskohlii extract (n = 15) or a placebo twice daily for 12 weeks. All participants were advised to follow a hypocaloric diet throughout the study.
Small clinical studies suggest that forskolin may help weight management or reduce asthma attacks. Recent randomized clinical trials specifically on standardized Coleus forskohlii extracts are limited.
In an open-label study, 15 healthy volunteers participated in an 8-week open-label study; subjects received 500 mg of CF extract (10% forskolin) twice a day with their meals. Significant decreases compared to baseline were detected after 8 weeks for BMI, body weight, and fat content. However, the open-label design and small sample limit the generalizability of these findings.
Evidence level: Moderate for andrographolide (human studies); preclinical/limited clinical for triptolide (restricted by toxicity)
Diterpenes and their derivatives have many biological activities, including anti-inflammatory and immunomodulatory effects. To date, several diterpenes, diterpenoids, and their laboratory-derived products have been demonstrated for antiarthritic activities. A systematic review searched 2,708 published records across PubMed, Science Direct, Google Scholar, and ClinicalTrials.gov. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways.
Evidence level: Predominantly preclinical; limited human clinical data
A review article critically discussed the literature on antidiabetic diterpenes published from 1997 up to September 2021. All the tested pimaranes consistently showed good activity in preclinical evaluations against diabetes. Inhibitions of α-glucosidase and protein tyrosine phosphatase 1B (PTP 1B) activities and PPAR-γ agonistic property were the most frequently used models for studying the antidiabetic activity of diterpenes. Human clinical evidence in this area remains sparse; most robust data derive from in vitro and animal studies.
Evidence level: Primarily in vitro; no large human RCTs
Phenolic diterpenes such as carnosic acid and carnosol disrupt microbial metabolism and cell integrity, while rosmarinic acid adds potent antibacterial and antifungal effects through antioxidant and enzyme-inhibitory mechanisms. Andrographolide was found to have a significant inhibitory effect on the biofilm of Pseudomonas aeruginosa and a synergistic antibacterial effect with azithromycin. These findings are in vitro and require validation in clinical settings.
Evidence level: Primarily in vitro and limited clinical data
Recent studies have found that andrographolide has a significant inhibitory effect on the replication process of the chikungunya virus (CHIKV), a mosquito-borne alphavirus. Andrographolide showed good inhibition of CHIKV infection and reduced virus production by approximately 3 log10 with a 50% EC50 of 77 µM without cytotoxicity. Time-of-addition and RNA transfection studies showed that andrographolide affected CHIKV replication, and the activity was shown to be cell type independent.
A phase 1 study of andrographolide in patients who were HIV-positive showed no effect on viral replication after 6 weeks, despite increased CD4+ counts. However, adverse reactions (e.g., headache, fatigue, rash, bitter/metallic taste, diarrhea, pruritus, decreased sex drive) required interruption of the study.
Evidence level: Strong regulatory approval, subsequently discontinued
An ingenane ester from Euphorbia peplus, ingenol 3-angelate (ingenol mebutate, PEP005, Picato®, LEO Pharma), was authorized by the FDA in 2012 and the EMA in 2013 to treat actinic keratoses. However, due to negative side effects, this medication was subsequently discontinued.
There has been a large increase in the number of studies regarding the antitumor activity of carnosic acid, carnosol, rosmarinic acid, and ursolic acid over recent years. Breast cancers, melanoma, colon cancer, liver carcinoma and leukemia have been the most studied. These findings remain predominantly preclinical. Many members of the terpene family have entered various phases of clinical trials, and some have been incorporated into the backbone of modern medicine, e.g., paclitaxel. A novel diterpenoid from Euphorbia resinifera, resiniferatoxin, a daphnane orthoester and strong capsaicin receptor agonist, is being tested in a phase III clinical study for the treatment of overactive bladders and chronic pain.
The following dosages are those specifically reported in cited studies and should not be interpreted as clinical recommendations.
Triptolide's clinical potential is limited by a narrow therapeutic window and multiple organ toxicity, especially hepatotoxicity. It is well known that triptolide has a small margin between the therapeutic and toxic doses, and could cause serious toxicity on digestive, reproductive, urogenital and blood circulatory systems. Among all the organs, the liver is one of the most remarkable targets of triptolide-induced toxicities. Many studies have shown that various extracts of TWHF containing triptolide could lead to liver injury in animals and humans. Its hepatotoxicity has limited its clinical application.
In 9,490 participants using andrographolide derivative injections, 383 (4.04%) reported adverse drug reactions. The safety profile of oral A. paniculata is favorable, though the significant risks associated with injectable derivatives warrant caution and separate evaluation. In one COVID-19 study, one participant in the A. paniculata group developed hyperkalemia.
Dose-limiting toxicity is myelosuppression with reversible granulocytopenia, anemia, and thrombocytopenia. Allergic reactions occur in up to 8% of patients receiving paclitaxel as an intravenous infusion over 6 to 24 hours. These can be acute anaphylactoid reactions including flushing, hypotension, and bronchospasm; dermatitis and pruritus are also observed.
Although anti-inflammatory and blood-pressure lowering effects have been shown in the laboratory setting, very few clinical trials have been conducted. Safety concerns include hypotension and increased bleeding risk when combined with anticoagulants or antiplatelet drugs. More studies are needed to determine safety and effectiveness for various conditions in humans.
Researchers have long been concerned with the potential beneficial or harmful effects of diterpenoid alkaloids due to their structural complexity, which accounts for their use as pharmaceuticals as well as their reputation as toxic substances. Compounds belonging to this unique family of natural products exhibit a broad spectrum of biological activities. Some of these compounds are on the list of clinical drugs, while others act as incredibly potent neurotoxins.
As a class, diterpenes can exert significant pharmacological effects on CYP450 enzyme systems, relevant to drug-drug interactions. Triptolide, for example, is an inducer of CYP2E1 via a time-dependent activation mechanism, which has the potential to alter the metabolism of co-administered drugs. By assistance of medicinal chemistry, structure-activity relationships, and semi-synthesis techniques, isolated diterpene compounds have sufficient potential to be used in drug development, but the same structural diversity that confers therapeutic potential also makes toxicological profiles highly compound-specific and not generalizable across the class.
Ingenol mebutate (Picato®) was authorized by the FDA in 2012 and the EMA in 2013 to treat actinic keratoses. However, due to negative side effects, this medication was subsequently discontinued. This case underscores the importance of post-approval pharmacovigilance even for approved diterpene-derived pharmaceuticals.
Health conditions that Diterpenes may help support.
Body systems that Diterpenes may help support.
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