Synonym name: Cardidigin; Crystodigin; Digisidin; Purodigin; Unidigin; Digitrin; Carditoxin
Catalogue No.: BP0489
Cas No.: 71-63-6
Formula: C₄₁H₆₄O₁₃
Mol Weight: 764.95
Botanical Source: From Digitalis purpurea, Digitalis lanata, Digitalis grandiflora, Digitalis ferruginea, Digitalis thapsi, Digitalis ciliata, Digitalis heywoodii and others

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams.

For Reference Standard and R&D, Not for Human Use Directly.
Inquire for bulk scale.

HPLC of Digitoxin

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Digitoxin is a classic natural cardiac glycoside, first isolated from plants of the Polygonatum genus. Due to its significant cardiac pharmacological activity, it is widely used in the treatment of heart failure. In recent years, with the advancement of natural product pharmacology and molecular biology techniques, the mechanism of action and potential anti-tumor activity of iridoid glycosides have attracted high attention from the scientific research community. Research has shown that iridoid glycosides not only exert cardioprotective effects by regulating intracellular calcium homeostasis, but also induce apoptosis, block cell cycle, and inhibit inflammatory responses in various tumor cells, demonstrating their potential as anticancer agents and immunomodulators.

This article will provide a systematic review of the chemical structure and physicochemical properties, plant sources, and extraction methods of digitalis toxin glycosides, with a focus on their pharmacological activity and mechanism of action. Combined with pharmacological parameters and pharmacokinetic characteristics, it will explore their clinical application prospects and future research directions, aiming to provide theoretical basis and research ideas for the in-depth development and clinical translation of this natural product.

Chemical structure and physicochemical properties

The molecular formula of Yangdi Huangdu glycoside is C41H64O13, with a molecular weight of 764.95 and a CAS number of 71-63-6. Its chemical structure belongs to the class of cardiac glycosides, with a steroid structure at its core, connected by a lactone ring and multiple glycoside residues. The specific structural features include:

• Steroid nucleus Having a typical four ring steroid skeleton, endowing it with a rigid conformation.
• Lactone ring The five membered α, β - unsaturated lactone ring located at position C17 is the key structural group for its biological activity.
• Glycoside part Composed of three numeric sugar residues, connected to the C3 position of steroids through glycosidic bonds, affecting their water solubility and bioavailability.

In terms of physical and chemical properties, the LogP value of iridoid glycosides is 2.5125, indicating that they have moderate lipid solubility and are conducive to membrane penetration. The polar surface area (TPSA) is 182.83 Å ², indicating high polarity and low water solubility (0.0242 mg/mL), which limits its oral absorption and bioavailability. The low penetration ability of the blood-brain barrier suggests its limited distribution in the central nervous system. The hERG channel inhibition test result was negative, indicating a low risk of cardiac toxicity, while the Ames mutagenicity test showed 0, indicating a low risk of genotoxicity.

Plant sources and extraction methods

The main source of digoxin is Digitalis spp., especially Digitalis purpurea and Digitalis lanata. Mao Di Huang plants are widely distributed in Europe, Asia, and North America, traditionally used to treat heart disease.

extraction method

The extraction of iridoid glycosides from Yangdi is usually carried out using the following steps:

1. Ingredient Preparation Collect plant leaves, dry and crush them.
2. Solvent extraction Extract glycoside compounds using methanol, ethanol, or water alcohol mixed solvents for extraction.
3. Liquid-liquid separation Separate non-polar impurities by using organic solvents such as ethyl acetate.
4. Column chromatography purification Using silica gel or C18 reverse phase column chromatography to separate and purify digitalis toxin glycosides based on polarity differences.
5. Crystallization Obtaining high-purity digitalis toxin glycoside through solvent crystallization.

In recent years, green and efficient technologies such as supercritical fluid extraction and microwave-assisted extraction have also been applied to the extraction of digitalis toxin glycosides, improving extraction efficiency and purity while reducing solvent usage.

Pharmacological activity research

The pharmacological activities of iridoid glycosides are diverse, covering aspects such as cardioprotection, anti-tumor, anti-inflammatory, and immune regulation.

Cardioprotective effect

As a classic cardiac glycoside, digoxin mainly inhibits the activity of Na ⁺/K ⁺ - ATPase on the myocardial cell membrane, leading to an increase in intracellular sodium ion concentration. This, in turn, increases intracellular calcium ion concentration through the sodium calcium exchange mechanism, enhancing myocardial contractility. The mechanism of inducing intracellular calcium uptake through the formation of transmembrane calcium channels provides a theoretical basis for the treatment of heart failure. In addition, berberine can activate the AMPK (PRKAA1) signaling pathway, regulate energy metabolism, and improve myocardial function.

Antitumor activity

In recent years, research on the use of iridoid glycosides in the field of cancer has rapidly developed. Its main anti-tumor mechanisms include:

• Inducing cell apoptosis Digitoxin induces programmed cell death in many cancer cell lines (such as lung cancer, breast cancer, liver cancer, etc.) by activating the endogenous apoptosis pathway.
• cell cycle arrest Can block the cell cycle in the G2/M phase and inhibit tumor cell proliferation.
• DNA damage Causing DNA double strand breaks (DSBs), activating DNA damage responses, and promoting cell apoptosis.
• Inhibit inflammatory response By inhibiting the cytokine storm of influenza and reducing the inflammatory response in the tumor microenvironment, it helps regulate tumor immunity.

Immune regulation and anti-inflammatory effects

Yangdi Huangdu glycoside can regulate various immune related targets, including EHMT2, PTPN1, MAOA, ESR2, etc., inhibit the release of pro-inflammatory cytokines, alleviate inflammatory reactions, and has potential anti-inflammatory and immune regulatory effects.

Mechanism of action and molecular targets

The multi-target mechanism of action of iridoid glycosides is complex, involving multiple biological processes such as cardioprotection, anti-tumor, and immune regulation.

Sodium potassium ATPase inhibition and calcium signaling regulation

Yangdi Huangdu glycoside specifically inhibits Na ⁺/K ⁺ - ATPase, leading to an increase in intracellular sodium ion concentration, affecting the sodium calcium exchange system, promoting calcium ion influx, and enhancing myocardial contractility. In addition, changes in calcium signaling are also involved in regulating cell apoptosis and cell cycle.

DNA damage and cell cycle regulation

Yangdi Huangdu glycoside can induce DNA double strand breaks (DSBs), activate the ATM/ATR signaling pathway, activate cell cycle checkpoints, block the cell cycle in the G2/M phase, and prevent tumor cell division and proliferation.

Key molecular targets

• AMPK (PRKAA1)As a regulator of energy metabolism, berberine activates AMPK, promotes metabolic homeostasis, and improves myocardial function.
• EHMT2 Histone methyltransferase regulates gene expression and participates in cell proliferation and apoptosis.
• APP Starch like precursor protein, involved in cellular signaling.
• PTPN1 Protein tyrosine phosphatase regulates multiple signaling pathways.
• MAOA Monoamine oxidase A is involved in neurotransmitter metabolism and regulation of the tumor microenvironment.
• ESR2 Estrogen receptor beta regulates cell proliferation and apoptosis.
• ABCB1、ABCG2 Multidrug resistance associated transporters affect drug efflux and resistance.
• ALOX15 Lipoxygenase is involved in inflammatory reactions.
• FEN1 DNA repair enzymes are involved in DNA replication and repair.

The regulation of these targets together constitutes a multidimensional pharmacological network of digitalis toxin glycosides.

Evaluation of drug properties and pharmacokinetics

The pharmacological evaluation of berberine shows that it has certain potential for drug development, but there are also some limitations.

Pharmaceutical properties parameters

• molecular weight 764.95, relatively large, may affect oral absorption.
• LogP 2.5125, moderate lipid solubility, conducive to cell membrane penetration.
• TPSA 182.83 Å ², high polarity, may limit penetration through biofilms.
• Water solubility：0.0242 mg/mL， Low, affecting solubility and bioavailability.
• Blood-brain barrier penetration Low, reducing the risk of central nervous system side effects.
• HERG inhibition Negative, low risk of cardiac toxicity.
• Ames test Negative, low risk of genotoxicity.

Pharmacokinetic characteristics

The oral absorption of berberine is slow and incomplete, and its bioavailability is limited. It is mainly metabolized in the body through the liver, with metabolic pathways involving glycoside hydrolysis and steroid skeleton modification. A longer half-life is beneficial for maintaining blood drug concentration, but it also increases the risk of drug accumulation. Excretion is mainly through bile and kidneys. Due to its low water solubility and large molecular weight, formulation design needs to be optimized to improve bioavailability.

Clinical application prospects and prospects

Yangdi Huangdu glycoside, as a traditional medicine for heart failure, has a long history of clinical application and clear therapeutic effects. With further research on its anti-tumor and immune regulatory effects, Yangdi Huangdu glycoside is expected to expand its clinical indications and become a multifunctional drug.

Heart Failure Treatment

Yangdi Huangdu glycoside remains an important treatment option for heart failure patients by regulating the calcium ion homeostasis of myocardial cells, enhancing myocardial contractility, and improving cardiac function. In the future, combining molecular targeted therapy with personalized medication strategies is expected to improve efficacy and safety.

Antitumor potential

Yangdi Huangdu glycoside has shown potential as an anti-cancer drug by inducing apoptosis, blocking cell cycle, and causing DNA damage in various tumor cells. By combining modern drug delivery systems (such as nanocarriers) and structural modifications, it is possible to overcome the shortcomings of poor water solubility and low bioavailability, and enhance anti-tumor activity.

Immune regulation and anti-inflammatory applications

The inhibitory effect of digitalis glycoside on inflammatory factor storm provides a new idea for its application in infectious diseases and autoimmune diseases. Future research can focus on its immune regulatory mechanisms and develop novel immune modulators.

Research and Development Challenges and Future Directions

• Drug safety Further evaluation is needed to assess the toxicity and side effects of long-term medication.
• Pharmacokinetic optimization Develop new formulations to improve oral bioavailability.
• Structural modification Improve pharmacological activity and selectivity through chemical modification.
• Research on multi-target mechanism Thoroughly analyze its functional network and guide clinical applications.
• clinical trial Conduct systematic clinical research to validate the efficacy and safety of its new indications.

Conclusion

Yangdi Huangdu glycoside, as a natural product with a long history, has played an important role in the treatment of heart failure due to its unique steroidal glycoside structure and diverse pharmacological activities. In recent years, its potential in anti-tumor, immune regulation, and anti-inflammatory aspects has gradually emerged, expanding its clinical application possibilities. Despite the challenges of poor water solubility and low bioavailability, with the development of modern drug research and development technology, the structural optimization and formulation improvement of digoxin will provide strong support for its clinical translation. In the future, combined with interdisciplinary research, berberine is expected to become a model of multifunctional natural medicine, contributing greater value to human health.