Introduction/Overview
Cephaline, CAS number 481-49-2, is a species derived from the family Menispermaceae, specifically the golden thread turtle（Stephania cephalantha Bisbenzylisoquinoline alkaloids extracted from plants such as Hayata in the genus Gentiana. Since its first isolation by Japanese scholar Hirasaburo Kondo in 1934, its unique chemical structure and extensive biological activity have attracted sustained attention from the pharmacological community. Over the course of nearly a century of research, Tripterygium wilfordii has demonstrated multiple pharmacological effects, including anti-inflammatory, antimalarial, anti radiation, anti fibrosis, and immune regulation. It is particularly renowned for its outstanding effect in reversing multidrug resistance (MDR) in tumors. In recent years, with the outbreak of the global COVID-19, stephanide has become a research hotspot again because of its remarkable anti SARS CoV-2 virus activity in vitro and in animal models, opening up a new track for its new use of old drugs. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, medicinal characteristics, and clinical application prospects of Tripterygium wilfordii Hook. f., in order to provide comprehensive academic references for the in-depth development and transformation research of this natural product.
Chemical structure and physicochemical properties
Qianjinteng Su is a bisbenzylisoquinoline alkaloid with a complex three-dimensional structure, with a molecular formula of C37H38N2O6 and a molecular weight of 606.7190. Its core structure is composed of two isoquinoline units connected by two benzyl bridges, forming a macrocyclic molecule with two chiral centers, usually in the form of a right-handed ligand. This rigid and flexible macrocyclic structure is the structural basis for its interactions with various biomolecules, such as proteins and membrane lipids.
From the perspective of physicochemical parameters related to drug properties, the lipid water partition coefficient (LogP) of Tripterygium wilfordii Hook. f. is 5.6138, indicating its high lipophilicity. Its topological polar surface area (TPSA) is 61.8600 Å ², which is relatively small. These two parameters together determine its extremely low water solubility (about 0.0013 mg/mL), which poses a challenge for its formulation development. High lipophilicity also indicates that it is easy to penetrate cell membranes and has a wide distribution in the body. Its blood-brain barrier (BBB) permeability is predicted to be "high", which provides potential advantages for its application in central nervous system related diseases such as neuroblastoma. However, drug safety warnings indicate that there is a potential risk of cardiac toxicity associated with resveratrol (hERG inhibition is "yes"), which needs to be closely monitored in subsequent development. The Ames test result is 0.0, indicating no mutagenicity, but a comprehensive genetic toxicity assessment still needs to be improved.
Plant sources and extraction methods
Qianjinteng extract mainly comes from the genus Qianjinteng in the family Menispermaceae（Stephania）Various plants, among which turtles are suspended with golden threads（S. cephalantha The aboveground part and root tuber of Hayata are the most abundant. This genus of plants is widely distributed in tropical and subtropical regions of Asia, including southern China, Japan, Thailand, and other places. It is traditionally used to treat fever, pain, and inflammatory diseases.
The extraction of Tripterygium wilfordii extract is usually carried out using organic solvent extraction combined with modern separation and purification techniques. The classic process is as follows: Dry and crushed plant materials (such as tubers) are extracted or refluxed using alcohols (such as methanol, ethanol) or mixed solvents (such as ammonia chloroform). After concentration, the extract is dissolved in acidic water (such as dilute hydrochloric acid), and acid insoluble substances are filtered out. Then, the pH is adjusted to alkaline using a base (such as ammonia water) to precipitate alkaloids or transfer them to organic phases (such as chloroform and ethyl acetate). The crude total alkali obtained is repeatedly separated and purified by methods such as silica gel column chromatography, high-performance liquid chromatography (HPLC), or preparative thin-layer chromatography to obtain high-purity quercetin monomer. In recent years, green and efficient technologies such as supercritical CO2 extraction and high-speed countercurrent chromatography have also been applied to their extraction and separation to improve yield and reduce the use of organic solvents.
Pharmacological activity research
Qianjin Teng Su has multi-target and multi pathway pharmacological activities, and its research has expanded from early anti-inflammatory and analgesic effects to multiple cutting-edge fields such as anti-tumor and antiviral effects.
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Antitumor activity: Senecin can inhibit the growth and promote apoptosis of many tumor cell lines (such as leukemia, liver cancer, lung cancer, breast cancer, etc.). Especially prominent is its ability to effectively reverse tumor multidrug resistance mediated by overexpression of P-glycoprotein (P-gp). Research has shown that Qianjin Tengsu non competitively inhibits the efflux pump function of P-gp, increases the accumulation of anticancer drugs (such as doxorubicin and vincristine) in drug-resistant tumor cells (such as K562/ADR), and significantly enhances the efficacy of chemotherapy drugs in vitro and xenograft mouse models.
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Antiviral activity: During the COVID-19, the anti SARS CoV-2 activity of celandine was widely confirmed. In vitro experiments have shown that it can inhibit virus proliferation in Vero E6 and other cells with micromolar potency (IC50=1.90 μ M, IC90=4.46 μ M). Its mechanism of action involves interfering with the fusion of virus and host cell membrane, inhibiting virus replication, and regulating host immune response. In addition, it also exhibits certain inhibitory activity against other viruses such as HIV, EB virus, etc.
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Anti inflammatory and immune regulatory activity Qianjinteng Su is a classic membrane stabilizer that can inhibit degranulation of mast cells and the release of various inflammatory mediators such as histamine, leukotrienes, TNF - α, IL-6. It exerts therapeutic effects in various acute and chronic inflammations (such as pneumonia, hepatitis, arthritis) and allergic disease models by regulating key inflammatory signaling pathways such as NF - κ B and MAPK.
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Other activities It also includes anti radiation damage, anti liver fibrosis and pulmonary fibrosis, analgesia, etc.
Mechanism of action and molecular targets
The multiple pharmacological activities of Tripterygium wilfordii stem from its interactions with various signaling molecules and pathways within cells. Taking neuroblastoma mentioned in the title as an example, its anti-tumor effect involves a complex target network:
- Apoptosis regulatory targets Qianjinteng Su can downregulate the expression of anti apoptotic proteins MCL1, BCL2, and BCL2L1 (Bcl xL), while upregulating the expression of pro apoptotic proteins such as p53 (TP53), disrupting mitochondrial membrane potential, leading to the release of cytochrome C, which in turn activates CASP9 and CASP8, ultimately triggering tumor cell apoptosis.
- signal transduction pathway It can inhibit the phosphorylation and activation of STAT3, and block the transcription of downstream genes that promote survival and proliferation. Meanwhile, by affecting the PI3K/Akt/mTOR pathway related to PIK3CA (the catalytic subunit of PI3K), cell growth and metabolism are inhibited.
- Stress and Cytoskeleton Qianjin Tengsu can inhibit the activity of hypoxia inducible factor HIF1A and interfere with the ability of tumors to adapt to the hypoxic microenvironment. In addition, it can also affect microtubule associated protein MAPT (Tau protein), which may interfere with cell mitosis and skeletal stability.
In terms of antiviral effects, its mechanism may be related to interfering with the binding of viral spike proteins to host cell ACE2 receptors, disrupting lipid raft structures to prevent virus invasion, and inserting lipophilic molecules into the viral envelope to disrupt its integrity. In the reversal of multidrug resistance, its main mechanism is the direct interaction with the P-gp drug binding pocket, which inhibits its ATPase activity. Inhibition of CYP450 enzymes (especially CYP3A4, 2E1, 2C9) suggests potential drug drug interaction risks.
Evaluation of drug properties and pharmacokinetics
Although the pharmacological activity of Tripterygium wilfordii Hook. f. is extensive, its medicinal properties face some challenges.
- Pharmacokinetic characteristics Animal pharmacokinetic studies have shown that the oral absorption of resveratrol is rapid but incomplete, and its absolute bioavailability is low, which is related to its low water solubility and first pass effect. It is widely distributed in the body, and due to its high lipophilicity, it is prone to accumulate in organs such as adipose tissue, liver, lungs, and can pass through the blood-brain barrier. It is mainly metabolized in the liver through the CYP450 enzyme system, and the metabolites are excreted through bile and urine. It itself is an inhibitor of CYP450 enzyme, which may lead to interactions with co administered drugs.
- Challenges and Strategies in Drug Development：
- Poor water solubility This is the primary issue that constrains its formulation development and in vivo efficacy. The current research strategies include preparing salts (such as hydrochloride salts), using cyclodextrin inclusion, and developing novel drug delivery systems such as liposomes, nanoparticles, and micelles to increase their solubility and bioavailability.
- Potential cardiac toxicity The inhibition of hERG potassium channels warns of the risk of inducing QT interval prolongation and apical torsion type ventricular tachycardia, and strict electrocardiographic safety evaluation is required in preclinical and clinical studies.
- Clear drug interaction risks As an inhibitor of key metabolic enzymes such as CYP3A4, when used in combination with drugs metabolized by the same enzymes (such as statins, some anticoagulants, immunosuppressants), the dosage should be carefully adjusted.
Clinical application prospects and prospects
The transformation of Tripterygium wilfordii extract from the laboratory to clinical practice is full of opportunities and challenges.
Conclusion
As a natural product with a long history of research, Tripterygium wilfordii extract continues to radiate new vitality due to its unique bisbenzylisoquinoline structure and multi-target properties. From early anti inflammation and analgesia to reversal of multidrug resistance, and then to today's anti COVID-19, its expanding pharmacological territory fully reflects the great value of natural products as drug lead compounds. Despite challenges such as water solubility, toxicity, and drug interactions in drug development, these obstacles are gradually being overcome through collaborative innovation in modern medicinal chemistry, pharmacy, and pharmacology. In the future, with the continuous deepening of basic research and the acceleration of clinical translation, Tripterygium wilfordii Hook. f. is expected to transform from an important pharmacological tool molecule into a clinically effective drug serving human health and treating various refractory diseases, continuing its glorious chapter from traditional medicinal plants to modern innovative drugs.
