Tetracyclic Oxindole Alkaloids (TOAs)
1. Identity: Botanical and Chemical Classification
Botanical Source
Tetracyclic oxindole alkaloids (TOAs) are a chemically distinct class of nitrogen-containing heterocyclic natural products found primarily in plants of the genus Uncaria, family Rubiaceae. The most pharmacologically and commercially significant source is Uncaria tomentosa (Willd. ex Schult.) DC., widely known as cat's claw or, in Latin America, as uña de gato. This tropical medicinal vine originates in the Amazon rainforest and other areas of South and Central America. A second South American species, Uncaria guianensis (Aublet) Gmelin, also produces oxindole alkaloids and shares overlapping traditional uses. Uncaria tomentosa is a member of the Rubiaceae plant family, native to the Amazon basin, and is widely distributed in Bolivia, Brazil, Colombia, Costa Rica, Ecuador, Guatemala, French Guiana, Guyana, Nicaragua, Panama, Peru, and Venezuela.
A second important plant source of tetracyclic oxindole alkaloids is Uncaria rhynchophylla (Miq.) Jacks., a species used in traditional Chinese medicine under the name Gouteng (or Gou Teng). Isocorynoxeine (ICN) is one of the major bioactive tetracyclic oxindole alkaloids found in Uncaria rhynchophylla, which is widely used for the treatment of hypertension, vascular dementia, and stroke.
Chemical Identity and Nomenclature
The alkaloids of Uncaria tomentosa contain a variety of structures classified into two groups: indole alkaloids and oxindole alkaloids. These groups were further classified into subclasses defined as tetracyclic and pentacyclic indoloquinolizidine, β-carboline-type, and tetracyclic and pentacyclic oxindole alkaloids. The prefix "tetracyclic" refers to the four-ring carbon skeletal framework of these molecules — in contrast to the five-ring pentacyclic oxindole alkaloids (POAs). Both series share an oxindole moiety (a 2-oxindole nitrogen-containing bicyclic ring system), with the tetracyclic series being structurally defined by the absence of the additional ring that distinguishes the POA subtype. The principal TOA compounds identified in U. tomentosa are rhynchophylline and isorhynchophylline, with their stereoisomers and related congeners corynoxeine, isocorynoxeine, corynoxine, and corynoxine B found in closely related Uncaria species. Tetracyclic oxindole alkaloids occurring in Uncaria tomentosa include isorhynchophylline and rhynchophylline.
Isorhynchophylline (IRN) and rhynchophylline (RN) are tetracyclic oxindole alkaloids accounting for more than 43% of the total alkaloid content in U. rhynchophylla and have been regarded as the major pharmacologically active components in the herb.
Chemotype Distinction: TOA vs. POA
A critically important phytochemical reality is that Uncaria tomentosa exists in two visually indistinguishable chemotypes with significantly different alkaloid compositions. Attempts to extract potentially therapeutic phytochemicals from this plant led to the discovery of two chemotypes with a different pattern of tetracyclic (TOA) and pentacyclic oxindole alkaloids (POA). More precisely, Uncaria tomentosa exists in three different chemotypes: two types with predominantly pentacyclic oxindole alkaloids (POAs), differentiated by their cis/trans isomerism, such as uncarine D (speciophylline), and one type with predominantly tetracyclic oxindole alkaloids (TOAs), such as rhynchophylline.
It was found that two chemotypes of Uncaria tomentosa with different alkaloid patterns occur in nature. The roots of one type contain pentacyclic oxindoles and the other contains tetracyclic oxindoles. This difference should be considered when the plant is used for medicinal applications. Tetracyclic oxindole alkaloids act on the central nervous system, whereas pentacyclic oxindole alkaloids affect the cellular immune system. Critically, recent studies have shown that the tetracyclic alkaloids exert antagonistic effects on the action of the pentacyclic alkaloids. Mixtures of these two types are therefore considered unsuitable for medicinal uses targeting immune modulation.
Tetracyclic oxindole alkaloids (TOA) act mostly on the central nervous system, while POA affect the immunocellular system.
Common Preparations and Forms
Cat's claw is a woody vine that grows wild in the Amazon rainforest and other tropical areas of Central and South America. The two most common species are U. tomentosa and U. guianensis. Most commercial preparations of cat's claw in the United States contain U. tomentosa. Cat's claw supplements can be taken as a liquid extract, capsule, powder, or tea. Raw bark and root bark are the primary plant parts used for extraction; the extract is usually made from the root bark, most commonly from U. tomentosa.
In the supplement market, products are marketed across a spectrum of standardization: some are standardized specifically for pentacyclic oxindole alkaloid content and certified to be free or low in TOAs (commercial names include Samento and Saventaro), while others are unstandardized whole-bark preparations that contain both TOA and POA alkaloids. A standardized extract consisting of less than 0.5% oxindole alkaloids and 8% to 10% carboxy alkyl esters has been used in doses of 250 to 300 mg in several clinical studies.
2. Traditional and Historical Use
Amazonian Indigenous Peoples
Cat's claw is a large, woody vine from the Amazon rainforest used medicinally by native tribes for at least 2,000 years. Cat's claw (U. tomentosa) has been used medicinally by the Aguaruna, Ashaninka, Cashibo, Conibo, and Shipibo tribes of Peru for at least 2,000 years. The Ashaninka Indian tribe in central Peru has the longest recorded history of use of the plant. Cat's claw was also used as a medicinal plant by the ancient Incas.
The Ashaninka use cat's claw to treat asthma, inflammations of the urinary tract, arthritis, rheumatism, and bone pain; to recover from childbirth; as a kidney cleanser; to cure deep wounds; to control inflammation and gastric ulcers; and for cancer. Indigenous tribes in Piura use cat's claw to treat tumors, inflammations, rheumatism, and gastric ulcers.
Preparations in traditional contexts have historically been made as decoctions of the inner bark or root bark — bark boiled or simmered in water for extended periods to yield a concentrated tea. In traditional medicine, U. tomentosa (cat's claw) is used as a treatment option against a wide range of health problems, including immune system deficiencies, neurodegenerative disorders, cancer, chronic fatigue syndrome, Crohn's disease, digestive complaints, parasitic and microbial infections, kidney conditions, inflammatory problems, irritable and leaky bowel syndrome.
Context of Traditional Use
In Peruvian–Amazonian traditional medicine, a medicinal plant is often used as part of la dieta (the diet) — a focused retreat involving dietary, social, and behavioural limitations along with the application of an appropriate herb such as cat's claw. Clinical research into the impact of medicinal plant use within la dieta is limited but indicates effectiveness.
Traditional Chinese Medicine (Gouteng)
The closely related species Uncaria rhynchophylla, known in Traditional Chinese Medicine (TCM) as Gouteng (literally "hook vine"), has been used for centuries in Chinese medical practice. The two alkaloids rhynchophylline and isorhynchophylline were reported to act mainly on the cardiovascular system and central nervous system, including effects on hypotension, bradycardia, antiarrhythmia, and protection of cerebral ischemia and sedation. This TCM context represents a distinct and historically independent tradition of use for the tetracyclic oxindole alkaloid-containing fraction.
3. Key Constituents and Phytochemistry
Full Phytochemical Composition of Uncaria tomentosa
The plant is rich in bioactive compounds including pentacyclic (POA) and tetracyclic (TOA) oxindole alkaloids, triterpenes, quinic acid esters, polyphenols (phenolic acids and proanthocyanidins), flavonoids, quinones, and glycosides, which have been attributed to its diverse pharmacological properties. It is well documented that the chemical composition of cat's claw includes 17 different alkaloids, quinovic acid glycosides, tannins, flavonoids, sterol fractions, and other compounds.
Specific Tetracyclic Oxindole Alkaloids
The major tetracyclic oxindole alkaloids identified in Uncaria species include:
- Rhynchophylline — a major TOA in both U. tomentosa and U. rhynchophylla
- Isorhynchophylline — the C-7 stereoisomer of rhynchophylline; together with rhynchophylline, it accounts for more than 43% of the total alkaloid content in U. rhynchophylla
- Corynoxeine and Isocorynoxeine — additional TOA congeners with documented neuroprotective activity
- Corynoxine and Corynoxine B — identified in U. rhynchophylla and studied for autophagy-inducing activity
- Mitraphylline and Isomitraphylline — found in the leaves and stems of U. tomentosa alongside dihydrocorynantheine and the indole alkaloids hirsutine and hirsuteine
The major alkaloids in related species are the tetracyclic oxindoles isorhynchophylline, rhynchophylline, isocorynoxeine, and corynoxeine, accompanied by minor yohimbine alkaloids.
Uncaria rhynchophylla contains major indole and oxindole alkaloids such as corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsuteine, hirsutine, and geissoschizine methyl ether.
4. Mechanisms of Action
Central Nervous System Activity
In contrast to the pentacyclic oxindole alkaloids, which are considered the primary immunomodulatory fraction, tetracyclic oxindole alkaloids are principally characterized by their actions on the central nervous system and cardiovascular system. Tetracyclic oxindole alkaloids (TOA) act on the central nervous system; for instance, isorhynchophylline can improve memory problems by increasing antioxidant levels, while exhibiting anti-inflammatory effects on brain tissues in mice.
Isorhynchophylline inhibited the 5-HT receptor in mice and in Xenopus oocytes expressing 5-HT2A or 5-HT2C receptors. Another alkaloid, isocorynoxeine, preferentially blocked the 5-HT2A receptor. Moreover, the antagonistic activity of isorhynchophylline at the 5-HT2A receptor was attributed to the configuration of the oxindole moiety of the compound.
These alkaloids exert neuroprotective effects against Alzheimer's disease, Parkinson's disease, and depression, and the mechanisms of these effects include anti-oxidant, anti-inflammatory, and neuromodulatory activities.
Neuroinflammatory Pathways
The tested compounds inhibited proinflammatory mediators such as NO, TNF-α, and interleukin (IL)-1β in LPS-activated N9 cells, by downregulating iNOS protein expression and attenuating the activation of NF-κB and ERK and p38 MAPKs. Rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine, and vincoside lactam from leaves of U. rhynchophylla inhibited NO release in LPS-activated primary rat cortical microglial cells (IC50: 13.7–19.0 μM).
Neuroprotective and Anti-Amyloid Mechanisms
Extracts containing rhynchophylline and isorhynchophylline improved cognitive function in mice with Alzheimer's-like symptoms and can inhibit the formation and destabilize the preformed fibrils of Aβ protein. Moreover, intracellular calcium overloading and tau protein hyperphosphorylation in PC12 cells can also be inhibited by rhynchophylline and isorhynchophylline.
Isorhynchophylline (20 or 40 mg/kg of body weight) improved cognition in rats treated with Aβ25–35 by suppressing neuronal apoptosis and tau protein hyperphosphorylation by lowering the GSK-3β activity and inducing PI3K/Akt signaling.
Isorhynchophylline (6.25, 12.5, 25, 50 μM) induced beclin 1-mediated autophagy to promote degradation of neuronal cell alpha-synuclein in N2a, SH-SY5Y, and PC12 cells, and also in primary cortical neurons.
Antagonism of Pentacyclic Oxindole Alkaloids
A well-documented and pharmacologically critical mechanism is the ability of TOAs to antagonize the immunomodulatory effects of POAs on human cells. In the study by Wurm et al. (1998), pentacyclic but not tetracyclic oxindole alkaloids from Uncaria tomentosa induced EA.hy926 endothelial cells to release factor(s) into the supernatant; this factor significantly enhanced proliferation of normal human resting or weakly activated B and T lymphocytes. Tetracyclic oxindole alkaloids dose-dependently reduce the activity of pentacyclic oxindole alkaloids on human endothelial cells.
Drug Transporter Modulation
Studies investigating the effect of U. tomentosa extract and its major oxindole alkaloids on multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters found that the UT extract significantly inhibited all ABC transporters and the majority of the SLC transporters tested. Of the investigated oxindole alkaloids, isopteropodine significantly inhibited OATP, OCT1 and OCT2, OAT3, ENT4, MDR1, and BCRP transporters.
5. Scientific Evidence by Area of Use
5.1 Arthritis (Osteoarthritis and Rheumatoid Arthritis)
Today, cat's claw is promoted for osteoarthritis, rheumatoid arthritis, cancer, viral infections, and other conditions. This remains the most clinically investigated area, though the evidence base is modest.
Osteoarthritis: Among 45 patients with painful osteoarthritis of the knee treated with cat's claw (100 mg once daily) or placebo for 4 weeks, pain scores decreased more with cat's claw, but night-time pain and swelling did not change; cat's claw was well tolerated and there were no serious adverse events or changes in serum ALT and AST values during treatment.
Rheumatoid Arthritis: In a small randomized trial (N = 40), U. tomentosa extract resulted in a reduction in the number of painful joints in patients with rheumatoid arthritis compared with placebo. Specifically, the extract of U. tomentosa, free from tetracyclic oxindole alkaloids, was effective in treating patients with rheumatoid arthritis. Patients treated with 60 mg of the extract showed a reduction of up to 53.2% in joint pain compared to the placebo group, which only had a 24.1% reduction in pain.
In one trial, 40 participants with rheumatoid arthritis, all receiving conventional treatment with sulfasalazine or hydroxychloroquine, were randomly assigned to receive either cat's claw tablets (60 mg of Uncaria tomentosa) or placebo tablets once a day for 24 weeks (Phase A). Participants in both treatment groups were then invited to take cat's claw for an additional 28 weeks (Phase B), while continuing their usual treatment.
A 2010 systematic review identified 4 randomized controlled trials that studied cat's claw for osteo- or rheumatoid arthritis; 2 of the trials used the herb in combination with other herbs. Of the 2 using only cat's claw, one is the Piscoya osteoarthritis study and the second was a double-blind trial conducted in 45 men with osteoarthritis of the knee.
Evidence strength: There have been very few high-quality clinical trials of cat's claw. There is no conclusive scientific evidence based on studies in people that supports using cat's claw for any health purpose. Some research has been done in people on the effect of cat's claw on various conditions, but many of the studies did not use rigorous methods and did not include enough study participants to allow definite conclusions.
5.2 Neurodegeneration and Cognitive Function
This area of investigation concerns primarily the TOA fraction, particularly isorhynchophylline, rhynchophylline, corynoxeine, and isocorynoxeine, derived mainly from Uncaria rhynchophylla. Evidence is currently confined to in vitro and animal (preclinical) models.
The inhibitory effect of U. rhynchophylla on the aggregation of both Aβ and tau was confirmed in 3 × Tg mice with both Aβ and tau pathology.
Network pharmacology analysis identified 10 alkaloids from U. rhynchophylla corresponding to 127 targets correlated with amyloid-β (Aβ) pathology, tau pathology and the Alzheimer's disease pathway. Based on the number of targets correlated with AD pathophysiological processes, angustoline, angustidine, corynoxine and isocorynoxeine are highly likely to become key phytochemicals in AD treatment.
The tetracyclic oxindole alkaloid isorhynchophylline (IRN) helps lessen cognitive impairment in preclinical models. However, no human clinical trials have yet confirmed these neuroprotective effects specifically for isolated TOA compounds. The current body of evidence is animal and cell-based only.
5.3 Cardiovascular Effects
Rhynchophylline and isorhynchophylline were reported to act on the cardiovascular system and central nervous system, including effects on hypotension, bradycardia, antiarrhythmia, and protection of cerebral ischemia and sedation. These effects have been described in preclinical studies but have not been validated in controlled human clinical trials specifically targeting isolated TOAs.
5.4 Immune Modulation and Inflammation
This area is considerably more complex for the TOA fraction specifically. While cat's claw as a whole has immunomodulatory properties, the immunostimulatory activity is primarily attributed to the pentacyclic oxindole alkaloids. Most of the scientific research has centered on pentacyclic oxindole alkaloids, which are considered the primary immunostimulatory constituents. There is limited direct evidence that tetracyclic oxindole alkaloids themselves possess significant immunostimulatory properties in humans.
Interestingly, U. tomentosa extracts can either stimulate or inhibit the release of different cytokines, depending on the animal's health status or the modeled disease. The TOAs specifically have been observed in some in vitro assays to inhibit proinflammatory cytokines, but regarding the effectiveness of pentacyclic oxindole alkaloids in reducing inflammatory processes, the results are conflicting, and the same interpretive caution applies to TOA-specific studies.
In one study, the presence of oxindole or pentacyclic alkaloids did not influence the antioxidant and anti-inflammatory properties of cat's claw extracts, suggesting that other phytoconstituents (such as proanthocyanidins) may contribute substantially to observed anti-inflammatory effects regardless of alkaloid chemotype.
5.5 Cancer-Adjuvant and Cytotoxic Activity
The most promising cytotoxic findings for U. tomentosa were observed for crude aqueous bark extracts against squamous cell carcinoma and pentacyclic oxindole alkaloid (POA)-rich extracts against prostate cancer and leukemia. In contrast, tetracyclic oxindole alkaloid (TOA)- and proanthocyanidin (PAC)-rich fractions showed limited cytotoxicity.
One controlled clinical trial examined U. tomentosa as a chemotherapy adjuvant: this randomized clinical trial assessed the effectiveness of Uncaria tomentosa in reducing the adverse effects of chemotherapy. Patients with Invasive Ductal Carcinoma—Stage II, who underwent FAC chemotherapy (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: one received chemotherapy plus 300 mg dry U. tomentosa extract per day and the other received chemotherapy only. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. The authors concluded that Ut is an effective adjuvant treatment for breast cancer. However, this trial evaluated a whole standardized extract, not isolated TOA fractions, limiting conclusions specifically about the TOA subclass.
Evidence strength: U. tomentosa has potential as a source of selective anticancer agents, particularly through crude aqueous bark and POA-rich extracts. The observed cytotoxic effects vary considerably depending on the extraction method and chemical composition, underscoring the need for standardization in future studies. Further standardized studies and mechanistic investigations are required to validate its therapeutic potential for cancer treatment.
5.6 Antiviral Activity
Oxindole alkaloids (POA and TOA) have been recognized as fingerprint compounds of Uncaria tomentosa in some pharmacopeias, and several pharmacological activities are linked to this class. It has been demonstrated that Uncaria tomentosa exerts an antiviral effect on human monocytes infected with dengue virus 2 (DENV-2) and herpes simplex virus type 1 (HSV-1). These findings are from in vitro and small clinical settings. Clinical trials are few, and those that exist often study mixed extracts rather than isolated tetracyclic oxindole alkaloids.
5.7 Anti-HIV Activity
Together with isorhynchophylline and corynoxine, two new oxindole alkaloids, macrophyllines C and D, were isolated from Uncaria macrophylla; macrophyllines D, isorhynchophylline, and corynoxine showed anti-HIV activities with EC50 values of 11.31 ± 3.29 μM, 18.77 ± 6.14 μM, and 30.02 ± 3.73 μM, respectively. This is in vitro evidence only; no clinical trials have evaluated TOAs for HIV treatment.
6. Body Systems and Health Areas of Association
- Central nervous system: TOAs interact with serotonin receptor subtypes (5-HT2A, 5-HT2C) and modulate neuroinflammatory pathways; preclinical evidence for neuroprotection in Alzheimer's and Parkinson's disease models.
- Immune system: Mixed activity — TOAs antagonize POA-mediated lymphocyte proliferation; overall cat's claw preparations modulate cytokine profiles and phagocytic activity, though the role of TOAs specifically is attenuating rather than stimulatory.
- Musculoskeletal system: Clinical trial evidence (small, preliminary) supports reduction of painful joints and inflammation in osteoarthritis and rheumatoid arthritis, primarily attributed to TOA-free or POA-dominant extracts.
- Cardiovascular system: Preclinical evidence for hypotensive, antiarrhythmic, and vasodilatory effects; hirsutine (an indole alkaloid co-occurring with TOAs) has been characterized as a calcium channel blocker.
- Gastrointestinal system: Traditional use for gastric ulcers, gastritis, and Crohn's disease; limited clinical evidence.
- Oncology (supportive): One clinical trial demonstrated reduced chemotherapy-induced neutropenia with a whole standardized extract; TOA fraction alone does not demonstrate significant cytotoxicity.
7. Dosage Forms and Reported Dosages
Dosages reported in published research and clinical trials vary substantially depending on the extract type, standardization, and therapeutic target. The following figures are sourced directly from documented studies and reviews:
- 100 mg once daily of freeze-dried cat's claw for 4 weeks in a trial of 45 patients with osteoarthritis of the knee.
- 30 mg daily of cat's claw vs. placebo in 40 patients with rheumatoid arthritis; adverse events were uncommon and minor, the most common being dyspepsia and pruritus.
- 60 mg once daily in a 24-week rheumatoid arthritis trial of 40 participants receiving concurrent standard disease-modifying therapy.
- 300 mg dry extract per day in a randomized clinical trial of breast cancer patients undergoing FAC chemotherapy.
- A standardized extract with less than 0.5% oxindole alkaloids and 8–10% carboxy alkyl esters has been used in doses of 250 to 300 mg in several clinical studies.
For preclinical TOA-specific studies in animals: Isorhynchophylline at 20 or 40 mg/kg of body weight improved cognition in rats treated with Aβ25–35 by suppressing neuronal apoptosis and tau protein hyperphosphorylation. Animal dosages are not directly translatable to human therapeutic doses.
8. Safety Considerations and Drug Interactions
General Tolerability
Human studies ranging from four to 52 weeks showed side effects that were similar to the placebo given. Patients reported abdominal pain, anaemia, diarrhoea, and nausea, which were thought to be related to disease progression rather than the supplement itself. Cat's claw has not been implicated in causing liver injury in documented case reports catalogued in the NIH LiverTox database.
Reported Adverse Effects
Cat's claw shows several adverse effects including nausea, acute renal failure, stomach discomfort, hormonal effects, diarrhea, hepatotoxicity, and neuropathy. These events have been reported primarily in case reports rather than systematically controlled trials.
Uncaria tomentosa has several traditional uses including gastritis, rheumatism, cirrhosis, gonorrhea, and cancers of the female genital tract. The use of this plant has been associated with development of acute interstitial nephritis leading to acute renal failure in case reports.
Contraindications
Based on pharmacological properties and available case data, the following contraindications and precautions have been documented in the literature:
- Not for use in pregnancy; avoid in children due to lack of safety data; avoid if trying to conceive due to mild contraceptive properties.
- Avoid in autoimmune conditions (unless otherwise advised); avoid in haemorrhagic disorders; avoid in kidney disease; not for use in patients with leukaemia.
- Not recommended in patients with low blood pressure due to hypotensive action.
Drug–Drug and Herb–Drug Interactions
There are theoretical reasons to suspect that cat's claw might interact with anticoagulant, antiplatelet, and blood pressure drugs, and other supplements as well.
Cat's claw is contraindicated to be used with anticoagulants, antihypertensive, and immunosuppressant drugs.
The most common mechanism leading to herb–drug interactions is the inhibition and/or induction of transport proteins and drug-metabolizing enzymes by herbal ingredients, causing changes in the pharmacokinetic disposition of the victim drug. Uncaria tomentosa has been studied for its potential interactions via this mechanism. The UT extract significantly inhibited all ABC transporters and the majority of the SLC transporters tested, and isopteropodine specifically inhibited multiple transporters including OATP, OCT1, OCT2, OAT3, ENT4, MDR1, and BCRP.
CYP enzyme inhibition has also been documented: cat's claw inhibits microsomal CYP 3A4 activity, increasing serum levels of drugs metabolized by CYP 3A4, such as non-nucleoside reverse-transcriptase inhibitors, cyclosporine, and some benzodiazepines, and may interact with anticancer agents such as paclitaxel, antifungals like ketoconazole, antiviral drugs, and oral contraceptives.
The TOA–POA Antagonism as a Safety and Efficacy Consideration
The second chemotype of U. tomentosa contains predominantly TOAs, both with or without a considerable amount of POAs. The TOAs are believed to be POA antagonists with respect to the POAs' desirable immunomodulatory effects. Thus, the determination of the chemotype is crucially important in the plant's analysis and processing for pharmaceutical preparation.
The observed cytotoxic and pharmacological effects vary considerably depending on the extraction method and chemical composition, underscoring the need for standardization in future studies.
References
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