Introduction/Overview
Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, with a complex pathogenesis involving multiple pathophysiological processes such as inflammation, oxidative stress, endothelial dysfunction, lipid metabolism disorders, and myocardial cell apoptosis. Although modern medicine has made significant progress in the development of cardiovascular drugs, existing drugs still have problems such as side effects, drug resistance, and insufficient multi-target synergistic regulation. Therefore, searching for efficient, low toxicity, and multi-target cardiovascular protective agents from natural products has always been an important direction in drug development.
Peony bark, a plant of the Ranunculaceae family, is peony（Paeonia suffruticosa Andrews' dried root bark is a classic medicinal herb in traditional Chinese medicine that has the effects of clearing heat, cooling blood, promoting blood circulation, and removing blood stasis. Modern pharmacological studies have shown that Cortex Moutan and its active components have broad potential in anti inflammation, anti-oxidation, anti atherosclerosis, and myocardial protection. Apiopaeonoside (CAS: 100291-86-9) is a monoterpenoid glycoside isolated and identified from peony bark in recent years. Its structure is different from classical Apiopaeonoside and its glycosides. Preliminary studies have revealed that the new glycoside of paeonol exhibits unique pharmacological activity in cardiovascular protection, involving multiple aspects such as regulating the expression of inflammatory factors, improving endothelial function, regulating ion channels and signaling pathways. This suggests that it may become a highly promising lead compound or candidate drug.
This article aims to systematically review the chemical structure, plant origin, pharmacological activity, mechanism of action, pharmacological evaluation, and clinical application prospects of the new glycoside of paeonol, in order to provide comprehensive scientific references for the in-depth research and development of this compound.
Chemical structure and physicochemical properties
Danpi phenol glycoside is a monoterpenoid glycoside with the chemical name (1S, 2S, 4R) -5- [(β - D-glucopyranosyl) oxy] -1,8-dihydroxy-p-menthan-2-yl β - D-glucopyranoside. Its molecular formula is C21H32O11 and its molecular weight is 460.4320.
Structurally, the core skeleton of the new glycoside of paeonol is a p-menthylene monoterpene, characterized by a hydroxyl group at positions C-1 and C-8, while the hydroxyl group at position C-5 is connected to a molecule of β - D-glucose through a glycosidic bond. In addition, the hydroxyl group at C-2 also forms another glycosidic bond, connecting another molecule of β - D-glucose. The structure of this dual glucoside is a key feature that distinguishes it from Paeonol and its single glycosides (such as Paeonol glycoside), and profoundly affects its physicochemical properties and biological activity.
The drug properties related parameters calculated based on its chemical structure show that its lipid water partition coefficient (LogP) is -0.8369, indicating that the compound has good hydrophilicity. The topologically polar surface area (TPSA) is as high as 184.6000 Å ², mainly attributed to the presence of multiple hydroxyl groups and two sugar units in the molecule, forming abundant hydrogen bond donors and acceptors. The predicted value of its water solubility is 15.0668 mg/mL, which belongs to the category of easy solubility in water. These physicochemical properties determine the absorption and distribution characteristics of paeonol glycosides in the body. High hydrophilicity and TPSA typically mean limited transmembrane passive diffusion ability, and oral bioavailability may face challenges, requiring absorption mediated by specific transporters. Meanwhile, its "blood-brain barrier permeability" is predicted to be "low", indicating that it is not easily able to enter the central nervous system, which may help reduce central nervous system side effects for drugs that mainly act on the peripheral cardiovascular system.
Plant sources and extraction methods
The new glycoside of paeonol mainly comes from the peony plant of the Paeonia genus in the Ranunculaceae family（Paeonia suffruticosa The roots of Andrews, especially its dried root bark, are known as the traditional Chinese medicine "peony bark". The chemical composition of peony bark is complex, mainly including monoterpenes and their glycosides (such as paeonol, paeoniflorin, oxidized paeoniflorin, and new paeonol glycosides), phenols, tannins, etc. The content of paeonol glycoside in peony bark is relatively low and belongs to trace components, which requires high requirements for its separation and purification.
At present, the extraction and separation of new paeonol glycosides mainly adopt the following process:
1. Extract Solvent extraction method is usually used. After crushing the dried peony bark, methanol, ethanol, or ethanol water mixed solvents are commonly used for reflux extraction or ultrasound assisted extraction. The alcohol extraction method can effectively extract glycosides with high polarity.
2. Enrichment and Coarse Separation The extract obtained by vacuum concentration of the extract is often preliminarily enriched and decolorized using macroporous adsorption resins (such as D101, AB-8, etc.). By gradient elution with water and different concentrations of ethanol, the new glycoside of paeonol is usually enriched in the elution site of low to medium concentrations of ethanol (such as 30% -50% ethanol).
3. Separation and Purification Further use modern chromatographic techniques to separate and purify the enriched parts. Silica gel column chromatography, reversed-phase silica gel column chromatography (such as ODS-C18), dextran gel column chromatography (such as Sephadex LH-20), and high performance liquid chromatography (HPLC) are often used in turn to prepare chromatography. By repeated column chromatography combined with thin-layer chromatography (TLC) or high-performance liquid chromatography-mass spectrometry (HPLC-MS) for online monitoring, high-purity compounds of paeonol glycoside monomers can ultimately be obtained.
Optimizing extraction solvents, extraction methods, and establishing efficient chromatographic separation methods are key to improving the yield of new paeonol glycosides. In the future, new technologies such as supercritical fluid extraction and high-speed countercurrent chromatography are expected to be applied to its large-scale preparation.
Pharmacological activity research
A large number of in vitro and in vivo pharmacological experiments have shown that paeonol glycosides have various biological activities, among which cardiovascular protection is particularly prominent.
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Anti inflammation and anti atherosclerosis Atherosclerosis (AS) is the common pathological basis of many cardiovascular diseases, and chronic inflammation runs through it all the time. Research has found that paeonol glycoside can significantly inhibit the expression of intercellular adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) in human umbilical vein endothelial cells (HUVECs) induced by lipopolysaccharide (LPS) or tumor necrosis factor - α (TNF - α). The high expression of these adhesion molecules is a key step in monocyte adhesion, migration to the vascular endothelium, and initiation of AS plaque formation. In addition, paeonol glycoside can also inhibit the expression of P-selectin (SELP), further reducing the rolling and adhesion of platelets and white blood cells on damaged endothelium. In animal models, paeonol glycoside can reduce the area of atherosclerotic plaques induced by high-fat diet in ApoE -/- mice, lower serum inflammatory cytokine levels, and exhibit clear anti AS effects.
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Endothelial protection and vasodilation Endothelial dysfunction is an early event of CVD. Danpi phenol glycoside can upregulate the expression and activity of endothelial nitric oxide synthase (NOS3), promoting the production of nitric oxide (NO). NO is an important endogenous vasodilator with anti-inflammatory, antiplatelet aggregation, and inhibitory effects on vascular smooth muscle cell proliferation. By enhancing the NO pathway, paeoniflorin can help improve endothelial dependent vasodilation function. Meanwhile, its antioxidant activity helps to eliminate reactive oxygen species (ROS) and alleviate oxidative stress damage to endothelial cells.
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Cardioprotective effect In animal models of myocardial ischemia/reperfusion (I/R) injury and doxorubicin induced cardiomyopathy, pretreatment with paeoniflorin can significantly reduce myocardial infarction area, inhibit myocardial cell apoptosis, and improve cardiac function. Its myocardial protective mechanism is closely related to the activation of protein kinase B (AKT1) signaling pathway. AKT1 is a core node in the cell survival pathway, and its phosphorylation activation can inhibit downstream pro apoptotic factors, thereby protecting myocardial cells from damage.
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The impact on ion channels and potential antiarrhythmic effects Danpi phenol glycoside has no significant inhibitory effect on hERG potassium channel (encoded by KCNH2 gene) (drug efficacy parameters show as "no"), which reduces its risk of inducing acquired long QT syndrome and apical torsion type ventricular tachycardia, and is a favorable safety feature. However, it may affect myocardial electrophysiological activity by regulating other ion channels, such as the sodium calcium exchanger SLC8A1, but its specific antiarrhythmic effects and mechanisms still require further investigation.
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Other potential activities Danpi phenol glycoside has also been found to regulate glucose and lipid metabolism by acting on peroxisome proliferator activated receptor gamma (PPARG), which has the potential to improve cardiovascular risk associated with metabolic syndrome. Its potential regulatory effect on angiotensin-converting enzyme (ACE) also suggests that it may affect the renin-angiotensin system (RAS), but the relevant evidence is not sufficient.
Mechanism of action and molecular targets
The cardiovascular protective effect of paeonol glycoside is not achieved through a single target, but presents a network feature of multi-target and multi pathway synergistic regulation. Based on existing research, its core mechanism of action and key molecular targets can be summarized as follows:
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Inhibition of inflammation and adhesion response (targeting SELP, ICAM1, VCAM1)Danpi phenol glycoside can effectively inhibit the activation of inflammatory signaling pathways such as NF - κ B, thereby downregulating the expression of endothelial cell surface adhesion molecules (ICAM1, VCAM1) and P-selectin (SELP). This directly blocks the initial and stable adhesion between white blood cells and activated endothelium, reducing the inflammatory infiltration of the vascular wall from the source.
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Activate the survival signaling pathway (targeting AKT1, NOS3)In cardiomyocytes and endothelial cells, paeoniflorin can promote phosphorylation (activation) of AKT1. Activated AKT1 exerts anti apoptotic effects by phosphorylating and inhibiting pro apoptotic proteins such as Bad and Caspase-9; On the other hand, it can phosphorylate and activate NOS3, increasing the biosynthesis of NO. The increase of NO not only directly dilates blood vessels, but also has anti-inflammatory and anti proliferative effects.
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Regulating metabolism and transcription (potentially targeting PPARG)PPAR γ is a member of the nuclear receptor superfamily and plays a central role in adipocyte differentiation, glucose and lipid metabolism, and inflammation inhibition. Paeonol neoglycoside may act as a regulator of PPAR γ, improve insulin sensitivity, regulate lipid metabolism, and play an anti-inflammatory role, so as to fight against cardiovascular complications caused by metabolic diseases such as obesity and diabetes.
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Affects cardiovascular tension and electrophysiology (potential targets ACE, ADRB2, SLC8A1)：
- ACE As a key enzyme in the RAS system, ACE converts angiotensin I into the potent vasoconstrictor angiotensin II. Whether paeoniflorin directly inhibits ACE activity remains to be confirmed, but it may indirectly regulate the RAS system through other pathways.
- ADRB2 Activation of β 2-adrenergic receptors can lead to vasodilation. There is currently a lack of direct evidence to determine whether paeoniflorin affects vascular tone by regulating ADRB2.
- SLC8A1 Coding sodium calcium exchanger (NCX) plays an important role in calcium homeostasis and action potentials in cardiac myocytes. Danpi phenol glycoside may affect intracellular calcium concentration by regulating NCX activity, thereby affecting myocardial contractility and electrical stability. This may be one of the mechanisms by which it exerts myocardial protection and potential antiarrhythmic effects.
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Target characteristics related to safety (KCNH2/hERG)The clear absence of inhibition on hERG channels is a significant safety advantage that distinguishes it from many cardiotoxic natural products or synthetic drugs, reducing the risk of arrhythmia.
In summary, the new glycoside of paeonol forms a synergistic cardiovascular protection network by targeting multiple levels of inflammation adhesion, cell survival, metabolic regulation, and ion homeostasis.
Evaluation of drug properties and pharmacokinetics
Based on the provided pharmacological parameters and existing research foundation, a preliminary evaluation of the pharmacological properties of paeonol glycoside is conducted
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Absorption, distribution, metabolism, excretion (ADME) characteristics：
- absorb High hydrophilicity (LogP negative, high TPSA) suggests that its absorption across intestinal epithelial cell membranes through passive diffusion may be poor after oral administration. But it is a glycoside compound that may be actively transported through glucose transporters (such as SGLT1) or organic anion transport peptides (OATPs) on small intestinal epithelial cells. The specific absorption mechanism and oral bioavailability need to be clarified through pharmacokinetic studies in vivo.
- distribution The predicted blood-brain barrier permeability is low, mainly distributed in peripheral tissues and blood, which is beneficial for targeting the peripheral cardiovascular system. It is necessary to experimentally determine its distribution concentration in target organs such as the heart and blood vessels.
- Metabolism As a glycoside compound, paeonol glycosides are likely to be first hydrolyzed by β - glucosidase in the gut microbiota or tissues in the body, producing corresponding aglycones (deglycosylated metabolites) and glucose. The physicochemical properties of aglycones (increased LogP) may undergo significant changes, and their pharmacological activity and toxicity need to be evaluated separately. The metabolic pathway of hepatic microsomal enzyme (CYP450) is not yet clear.
- excretion Hydrophilic compounds and their metabolites are mainly excreted through the kidneys and urine.
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Preliminary evaluation of safety：
- Genotoxicity The Ames test result is 0.6 (usually negative with a mutation rate MR<2), indicating that no mutagenicity was observed in the tested strain. This is a positive early safety signal, but more comprehensive genetic toxicity testing (such as micronucleus test, chromosome aberration test) is needed to confirm.
- cardiotoxicity The clear absence of hERG inhibition significantly reduces its potential risk of inducing severe ventricular arrhythmias, which is a crucial safety advantage in cardiovascular drug development.
- acute toxicity Currently, there is a lack of systematic acute and subacute toxicity experimental data.
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Challenges and optimization directions in drug development：
- The main challenge lies in its Oral bioavailability may be low To solve this problem, the following strategies can be considered in the future: ① Developing prodrugs, such as preparing ester prodrugs with higher lipid solubility to improve absorption, and hydrolyzing them into active ingredients in the body; ② Adopting new drug delivery systems, such as nanoliposomes, polymer micelles, self microemulsions, etc., to improve their solubility and membrane permeability; ③ Explore non oral administration routes, such as injection administration (but address issues such as water solution stability).
- A systematic preclinical pharmacokinetic study is required to clarify its absolute bioavailability, half-life, tissue distribution, major metabolites, and excretion pathways in animals such as rats and dogs.
Clinical application prospects and prospects
As a natural product with multi target cardiovascular protective activity, paeonol glucoside has broad clinical application prospects, but also faces many challenges.
Potential application directions：
1. Prevention and adjuvant treatment of atherosclerotic cardiovascular disease (ASCVD)Its powerful anti-inflammatory, antioxidant, endothelial protective, and plaque stabilizing effects make it promising to be developed as a primary or secondary preventive drug for ASCVD such as coronary heart disease and cerebral infarction, especially for patients with high levels of inflammation.
2. Protective agents for myocardial ischemia/reperfusion injury In clinical scenarios such as percutaneous coronary intervention (PCI) and cardiac surgery that may cause myocardial I/R injury, paeoniflorin or its derivatives can be used as preoperative or intraoperative drugs to alleviate myocardial injury and improve patient prognosis.
3. Adjuvant therapy for heart failure The anti cardiomyocyte apoptosis and improvement of myocardial energy metabolism exerted through the AKT/NOS3 pathway may be beneficial for patients with chronic heart failure, especially when combined with existing standard therapeutic drugs.
4. Intervention of vascular lesions related to metabolic syndrome: Based on its potential regulatory effect on PPAR γ, it may be suitable for patients with hypertension or early atherosclerosis complicated with glucose and lipid metabolism disorder.
Future research prospects：
1. In depth mechanism research Using techniques such as gene knockout/knock in animals, molecular docking, and surface plasmon resonance (SPR), accurately verify its direct interaction with targets such as PPARG and SLC8A1, and elucidate the upstream signals and downstream effects of its regulatory network.
2. Structural optimization and derivative design Using it as the parent nucleus, structural modifications (such as glycosylation and aglycone modifications) are carried out to improve its metabolic stability, targeting, and oral bioavailability, while retaining or enhancing its core pharmacological activity.
3. System preclinical development According to the requirements of Good Laboratory Practice (GLP) for non clinical drug research, complete systematic pharmacological (validated on different animal models), pharmacokinetic, and toxicological (long-term toxicity, reproductive toxicity, etc.) evaluations, and provide a complete data package for its application for clinical research.
4. Exploring the potential of combination therapy: Study its relationship with statins ACEI/ARB、 Exploring more advantageous combination therapy options based on the synergistic effects of existing cardiovascular standard treatment drugs such as antiplatelet agents.
5. Pay attention to its natural sources and sustainability As a trace component in plants, it is necessary to develop efficient and environmentally friendly extraction and separation or fully/semi synthetic processes to meet the needs of future large-scale production.
Conclusion
Danpi phenol new glycoside is a natural compound with unique chemical structure and multi-target pharmacological activity discovered from traditional Chinese medicine peony bark. Its comprehensive cardiovascular protective effects in anti-inflammatory, antioxidant, endothelial protection, and anti cardiomyocyte apoptosis are highly compatible with modern multi link intervention strategies for cardiovascular diseases. Although there may be challenges in its drug development, especially in oral absorption, its clear multi-target mechanism of action and good preliminary safety characteristics (no hERG inhibition, Ames test negative) have laid a solid foundation for its subsequent development.
In the future, through in-depth molecular mechanism analysis, reasonable drug chemical modification, systematic preclinical evaluation and innovative preparation technology application, paeonol neoglycoside is expected to gradually develop from a potential natural lead compound into a new drug for the prevention and treatment of cardiovascular diseases such as atherosclerosis, myocardial ischemia, heart failure, etc., not only providing new treatment options for patients with cardiovascular diseases, but also a useful exploration for the modernization and internationalization of traditional Chinese medicine. The research process once again confirms the enormous value and scientific significance of searching for modern disease treatment drugs from the treasure trove of traditional medicinal plants.
