Yigangliu toxin glycoside: a natural anti-inflammatory candidate molecule derived from Xiangjiapi
1. Overview
Periplogenin 3- [O - β - glucopyranosyl - (1 → 4) - β - sarmentopyranoside] is a traditional medicinal plant derived from Periplogenin Xiangjiapi（Periploca sepium）Natural products of cardiac glycosides isolated from the middle. Its CAS number is 1253421-94-1, molecular formula is C36H56O13, and molecular weight is approximately 696.83 g/mol. As one of the characteristic active ingredients of plants in the genus Periplogenin, Periplogenin and its glycosides have long been used in traditional medicine to treat rheumatism, edema, and heart failure. Modern pharmacological research has revealed that the compound and its aglycone exhibit a wide range of biological activities beyond traditional cardiotonic effects, particularly in anti-inflammatory and immunomodulation The field shows enormous potential. Existing studies have shown that the glycoside of Periphyllum barbarum can exert a protective effect on thyroid toxicity and related cardiovascular problems by directly anti thyroid effects and inhibiting lipid peroxidation. Meanwhile, it can also inhibit abnormal proliferation of keratinocytes by inducing oxidative stress-induced necrotic apoptosis, thereby significantly improving skin lesions in a psoriasis like mouse model. These findings expand the research perspective of isorhamnoside from the traditional cardiovascular field to the treatment of autoimmune and inflammatory diseases, making it a multi-target natural lead compound worthy of further exploration.
2. Chemical structure and physicochemical properties
Yigangliu toxin glycoside belongs to C21 steroidal cardiac glycosides Class of compounds. Its structural core is the steroid nucleus (cyclopentane dihydrophenanthrene), and it is connected to an unsaturated pentagonal lactone ring (α, β - unsaturated γ - lactone) at position C17, which is a characteristic structure of cardiac glycosides and closely related to positive inotropic effects. The sugar chain part of this molecule is the key to its "differentiation" from other abscisic acid residuesβ - Salmonella sugar(β - sarmentopyranose) andβ - glucoseβ - glucopyranose is connected by a (1 → 4) glycosidic bond and then linked to the hydroxyl group at the C3 position of the glycoside through a glycosidic bond. This special disaccharide structure may affect its solubility, stability, and interaction with the target.
From the analysis of the provided pharmacological parameters:
- Molecular weight (MW)：696.83 g/mol， Slightly higher than the standard for conventional small molecule drugs (usually<500 Da), mainly due to its larger sugar moiety.
- Lipid water partition coefficient (LogP/LogD)1.33 indicates that the compound has moderate lipophilicity, which theoretically facilitates penetration of cell membranes, but does not lead to excessive metabolism or poor distribution due to high lipid solubility.
- Topological Polarity Surface Area (TPSA)Up to 193.83 Å ², mainly due to multiple hydroxyl groups in the molecule and oxygen atoms on the sugar ring. High TPSA is usually associated with Lower blood-brain barrier (BBB) penetration ability Related, this is consistent with the judgment of "BBB_permeability: low" in the parameter, indicating that it may not be suitable for the treatment of central nervous system diseases.
- Water solubility 0.1115 (unit not provided, usually on the order of mg/mL or mol/L), belongs to slightly soluble or poorly soluble, which is consistent with its larger molecular weight and glycosidic structure. Solubilization strategies may need to be considered during formulation development.
- Plasma protein binding rate (PPB)57.14%, belonging to the moderate level, means that about half of the molecules in the blood bind to plasma proteins (mainly albumin), which can affect their free concentration, distribution volume, and drug efficacy.
Overall, isorhamnoside is a medium molecular weight natural glycoside compound with high polarity and limited water solubility. Its pharmacokinetic properties may face challenges, but its structure provides a basis for optimizing activity targeting specific targets.
3. Plant sources and traditional applications
The plant source of isorhamnoside is Xiangjiapi, namely Gangliu（Periploca sepium Bunge's dried root bark belongs to the family Asclepiadaceae and the genus Salix. Xiangjiapi has a long history of medicinal use in China, first recorded in the "Shennong Bencao Jing" and classified as a medium grade product. It has a pungent and bitter taste, a warm nature, and is toxic. It belongs to the liver, kidney, and heart meridians. Its traditional functions are mainly Dispelling wind and dampness, strengthening muscles and bones, promoting diuresis and reducing swelling。
In clinical Chinese medicine, Xiangjiapi is commonly used for the treatment of:
1. Wind cold dampness rheumatism, joint spasms and pain Utilize its ability to dispel wind, dampness, unblock meridians, and relieve pain.
2. Weak waist and knees, weak muscles and bones Reflect its effect of strengthening muscles and bones.
3. Palpitations, shortness of breath, lower limb edema(Especially cardiogenic edema): This is a typical application of its "cardiotonic diuretic" effect. Although traditional medicine does not have the concept of "cardiac glycosides", its role in improving symptoms related to heart failure has been recognized in practice.
It is worth noting that Xiangjia Pi is emphasized in traditional applications due to its "toxicity"Processing attenuated drugs and Strictly control the dosage Modern pharmaceutical analysis has confirmed that its toxicity mainly comes from the various cardiac glycosides it contains, including paeoniflorin, paeoniflorin, etc. They have a strong excitatory effect on the myocardium, and excessive amounts can lead to arrhythmia and even cardiac arrest. As one of the components, the balance between the activity and toxicity of isorhamnoside is a core issue that needs to be carefully evaluated in modern drug development. Traditional application experience has pointed out its core functional systems (cardiovascular, immune inflammation) for modern research, while also warning of its potential safety risks.
4. Pharmacological activity and mechanism of action
Modern research has shown that the pharmacological activity of isorhamnoside and its aglycone, rhamnoside, goes far beyond its cardiotonic effect anti-inflammatory and immunomodulation The activity is particularly prominent. The database information shows that its function involves TNF、PTGS2、NFKB1、IL6、IL1B Five key targets clearly outline a classic pro-inflammatory signaling pathway network.
Analysis of the core mechanism of action:
-
Regulation of inflammatory signaling pathways：
- Targeting the NF - κ B pathway Nuclear factor kappa B (NF - κ B, encoded by the NFKB1 gene) is a core transcription factor in inflammatory response. Isorhamnoside may inhibit the nuclear translocation of NF - κ B by suppressing the activation of I κ B kinase (IKK) or preventing its degradation. Once NF - κ B is inhibited, the transcription of a series of downstream pro-inflammatory factors will be blocked.
- Downregulate key pro-inflammatory cytokines Tumor necrosis factor - α (TNF - α), interleukin-6 (IL-6), and interleukin-1 β (IL-1 β) are the most important downstream effector molecules of the NF - κ B pathway, playing a central role in acute phase response, fever, cell apoptosis, and immune cell recruitment. Yigangliu toxin glycoside can reduce the expression of these cytokines and directly alleviate inflammation at the effector level.
-
Inhibit the synthesis of inflammatory mediators：
- Inhibition of cyclooxygenase-2 (COX-2, encoded by the PTGS2 gene)COX-2 is a key enzyme that catalyzes the synthesis of prostaglandins (PGs) from arachidonic acid, particularly strongly induced in inflammatory sites. Prostaglandins (such as PGE2) are important mediators that cause pain, fever, and vasodilation. Yigangliu toxin glycoside achieves anti-inflammatory, analgesic, and antipyretic effects by inhibiting the expression of PTGS2 and reducing the production of prostaglandins.
-
Special mechanisms in psoriasis models：
The existing description mentions that the glycoside of Periphyllum erinaceus can induce HaCaT cells (human immortalized keratinocytes) to undergo apoptosis Oxidative stress-induced necrotic apoptosis One of the main pathological features of psoriasis is the excessive proliferation and abnormal differentiation of epidermal keratinocytes. By inducing these abnormally proliferating cells to undergo programmed cell death (necroptosis is one form), it can effectively slow down epidermal thickening and scale formation. At the same time, it inhibits the psoriasis like skin lesions induced by TPA (phorbol ester) and IMQ (imiquimod) in mouse models, further confirming its effectiveness through anti-inflammatory(Inhibiting the above cytokines) and Anti proliferation The dual pathway of inducing pathological cell death exerts therapeutic effects.
-
Protective effect on thyroid toxicity：
Gangliu toxin glycoside through Direct anti thyroid activity and Inhibition of lipid peroxidation (LPO) Make an impact. Excessive thyroid hormone (hyperthyroidism) can lead to metabolic hyperactivity, producing a large amount of reactive oxygen species (ROS), causing oxidative stress and lipid peroxidation, and damaging myocardial cells. Gangliu toxin glycoside may interfere with the synthesis or action of thyroid hormones on the one hand, and act as an antioxidant to alleviate oxidative stress, thereby protecting the heart from damage caused by hyperthyroidism.
Summarize its functional network Isorhamnoside may act as a multi-target regulator, upstream inhibiting key inflammatory signaling hubs such as NF - κ B, midstream reducing cytokine storms such as TNF - α, IL-6, IL-1 β, downstream inhibiting the production of inflammatory mediators such as COX-2/PGE2, and synergistically exerting therapeutic effects by inducing cell death in specific diseases such as psoriasis. This multi link and multi-target characteristic gives it unique advantages in treating complex inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, etc.
5. Evaluation of drug properties
Based on the provided parameters, we combine Lipinski's Five Rules Lipinski's Rule of Five (Ro5) and modern medicinal chemistry concepts provide a preliminary evaluation of the potential for the development of isosveratrol as a drug
-
Lipinski Five Rule Compliance：
- Molecular weight (MW)：696.83 > 500，violate Rule one.
- Lipid water partition coefficient (LogP)：1.33 < 5，Comply with Rule 2.
- Hydrogen bond donor (HBD)According to the structural formula, there are multiple hydroxyl groups on the sugar and glycoside groups, with a quantity greater than 5,violate Rule 3 (HBD>5).
- Hydrogen bond acceptor (HBA)The molecule contains multiple hydroxyl and sugar epoxy atoms, with a quantity far greater than 10,violate Rule 4 (HBA>10).
- Rotatable key There are multiple glycosidic bonds and steroid side chains in the molecule, and the number of rotatable bonds may be relatively high.
- Conclusion The serious violation of three of Lipinski's five rules (MW, HBD, HBA) by isorhamnoside usually indicates its Oral bioavailability may be low This is consistent with its higher TPSA and lower water solubility parameters.
-
Preliminary evaluation of pharmacokinetics and toxicity：
- Absorption and penetration The permeability (0.7355) and effective permeability (Peff: 0.5518) values of Caco-2 cells are both low, indicating that their intestinal absorption may be poor. This is consistent with its high polarity and high molecular weight characteristics.
- distribution The low penetration of BBB clearly rules out its potential as a central nervous system drug. The moderate plasma protein binding rate (57.14%) requires attention to its potential for drug drug interactions in subsequent studies.
- Metabolism and toxicity Ames test, chromosomal aberration test, hERG inhibition, skin/respiratory sensitization, phototoxicity and other indicators are all negative or "none/no",Preliminary indications suggest that its genetic toxicity and cardiotoxicity risks are relatively low This is a positive signal. However, serum biochemical indicators suggest that it has an impact on Alkaline phosphatase (ALK), aspartate aminotransferase (AST), alanine aminotransferase (ALT) Has an impact ("Yes"), which may be due to the presence of the compound or its metabolites Potential hepatotoxicity The markers need to be rigorously evaluated through animal experiments in preclinical studies.
- Feasibility of synthesis The synthetic accessibility score (SyneAccessibility: 5.6677) indicates that its synthesis is somewhat difficult, but extracting and isolating it from natural plants is currently the more feasible way to obtain it.
Comprehensive evaluation of drug properties Yigangliu toxin glycoside is a Clear activity but challenges in developing medicinal properties The lead compound. Its outstanding multi-target anti-inflammatory activity is its biggest advantage. However, poor drug properties (difficult oral absorption) and potential liver toxicity warnings are the main obstacles to its development. Future research directions may include:
- structural optimization Modify it through medicinal chemical methods, such as simplifying sugar chains, preparing glycosides (such as Periploma glycosides) or their derivatives, to reduce molecular weight, decrease polarity, improve membrane permeability, while retaining or enhancing anti-inflammatory activity.
- Exploration of administration routes: In view of its poor oral absorption, we can consider developing topical preparations (such as cream and gel for the treatment of psoriasis) or injections.
- In depth security evaluation Comprehensive preclinical toxicology studies must be systematically conducted, particularly in terms of hepatotoxicity, cardiotoxicity (although hERG negative, caution should be exercised regarding cardiac glycosides background), and long-term toxicity assessment.
6. Research Status and Application Prospects
At present, research on the toxic glycosides of Eriocheir sinensis is still in progress Preclinical stage Mainly focused on activity screening, preliminary exploration of mechanism of action, and plant chemical isolation. There has been relatively more research on its glycoside, namely the glycoside of Periploca diffusa, revealing its potential in anti-inflammatory, anti psoriasis, and cardioprotective effects, providing important references for the study of Periploca diffusa glycoside.
Research status：
1. basic research It has been preliminarily confirmed that its anti-inflammatory effect is related to key targets such as NF - κ B, TNF - α, COX-2, and its efficacy has been validated in cell and animal models, especially psoriasis models.
2. Chemical research The separation and identification of Xiangjiapi have been achieved, but its total synthesis route is complex, and natural extraction is still the main method at present.
3. Research on medicinal properties Just started, existing data suggests that there are bottlenecks in absorption and distribution, and there is a need to be vigilant about the risk of liver toxicity.
Application prospects and future directions：
1. As a candidate drug for treating autoimmune skin diseases Based on its significant effect in psoriasis like models, develop Topical preparations It is the fastest path to avoid systemic toxicity and achieve local therapeutic effects. New external delivery systems such as nanoemulsions and liposomes can be explored to enhance skin penetration and retention.
2. Structural optimization as an anti-inflammatory lead compound Pharmaceutical chemists can use it as a template to conduct systematic structure-activity relationship studies. The key optimization directions include: a) exploring whether glycosylation is an essential pharmacophore; b) Modify the steroid core or lactone ring to enhance activity and reduce toxicity; c) Prepare prodrugs to improve water solubility and oral bioavailability.
3. Exploring its immune regulatory mechanism in depth In addition to known pro-inflammatory targets, further research should be conducted on their regulatory effects on different subtypes of immune cells, such as T cells and macrophages, to clarify their therapeutic potential in a wider range of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
4. Strengthen systematic toxicology research This is an insurmountable step towards clinical application. It is necessary to design rigorous long-term toxicity, reproductive toxicity, and mutagenicity experiments, and clarify the specific mechanism of liver toxicity (whether it is caused by direct liver cell damage or metabolic activation), in order to provide a basis for determining the safety window.
Conclusion Yigangliu toxin glycoside is a treasure molecule discovered from traditional Chinese medicine Xiangjiapi. It carries the wisdom of traditional medicine and also faces strict tests in modern drug development. It is like a multi toothed key that can simultaneously act on multiple key nodes in the inflammatory network, making it uniquely attractive for treating complex inflammatory diseases. Although there are still thorns on the road to becoming a safe and effective modern drug, especially in terms of drug formulation and toxicity challenges, through interdisciplinary collaboration - combining natural product chemistry, pharmacology, pharmacokinetics, and toxicology - to conduct in-depth "abandonment" research on it (leveraging its multi-target efficacy advantages and abandoning its pharmacokinetic and toxicity disadvantages through structural modification), isoperidin and its derivatives are expected to provide new weapons for the treatment of inflammatory diseases in the future.
![Periplogenin 3-[O-β-glucopyranosyl-(1→4)-β-sarmentopyranoside]](/upload/0201/01/1253421-94-1.png)
