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Synonym name:
Catalogue No.: BP0075
Cas No.: 6559-91-7
Formula: C21H20O8
Mol Weight: 400.383
Botanical Source:
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.
Description:
4'-Demethylepipodophyllotoxin is an antimitotic agent which binds to monomeric tubulin, preventing micro-tubule polymerization. It is a potent inhibitor of microtubule assembly.
References:
Bioorg Med Chem. 2014 Jun 1;22(11):2998-3007.
A rational design strategy of the novel topoisomerase II inhibitors for the synthesis of the 4-O-(2-pyrazinecarboxylic)-4'-demethylepipodophyllotoxin with antitumor activity by diminishing the relaxation reaction of topoisomerase II-DNA decatenation.
A rational design strategy of the novel podophyllum topoisomerase II (Topo II) inhibitors for the synthesis of the esterification and amidation substituted 4'-Demethylepipodophyllotoxin (DMEP) derivates was developed in order to discover the potential antitumor prodrug. Firstly, according to the structure-activity relationship, drug combination principle and bioisosterism, the -COO- and the -NH- bond substituents at the 4 position of cycloparaffin would be a great modification direction to improve antitumor activity of 4'-Demethylepipodophyllotoxin (DMEP). Secondly, from the prodrug principle view, the esterification and amidation at the C-4 position of DMEP would be two useful structure modifications for improve solubility. Thirdly, from the activity pocket in Topo II-DNA cleavage complex point of view, a series of heterocyclic with pharmacological activity were chosen as module for improving antitumor activity by binding with Topo II. Finally, nine novel esterification and amidation DMEP derivates were designed and synthesized for the potential Topo II inhibitors with the superior biological activity.
METHODS AND RESULTS:
All the novel compounds exhibited promising in vitro antitumor activity, especially 4-O-(2-pyrazinecarboxylic)-4'-Demethylepipodophyllotoxin (compound 1). The antitumor activity of compound 1 against tumor cell line HeLa (i.e., the IC50 value of 0.60 ± 0.20 μM), A549 (i.e., the IC50 value of 3.83 ± 0.08 μM), HepG2 (i.e., the IC50 value of 1.21 ± 0.05 μM), and BGC-823 (i.e., the IC50 value of 4.15 ± 1.13 μM) was significantly improved by 66, 16, 12, and 6 times than that of the clinically important podophyllum anticancer drug etoposide (i.e., the IC50 values of 15.32 ± 0.10, 59.38 ± 0.77, 67.25 ± 7.05, and 30.74 ± 5.13 μM), respectively.
CONCLUSIONS:
Compound 1 could arrest HeLa cell cycle G2/M and induce apoptosis by strongly diminishing the relaxation reaction of Topo II-DNA decatenation. The correctness of rational drug design was strictly demonstrated by the bioactivity test.
Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃
131.4200
.4700
.1900
Low
No
No
No
Yes
No
Positive
4'-Demethylepipodophyllotoxin (CAS No.: 6559-91-7) is an important natural product, belonging to the family of organic heterotetracyclic compounds, and is the 9-anisomer of 4'-demethylepipodophyllotoxin. As a derivative of epipophylloxin compounds, this compound has attracted widespread attention due to its remarkable antitumor activity. Epipophylloxin and its derivatives hold an important position in the development of anticancer drugs. Related drugs such as etoposide and teniposide have been successfully applied in clinical treatment of various malignant tumors. 4'-Demethylphytoxin, as a structural analog, offers a potential molecular basis for the development of novel antitumor drugs due to its unique chemical configuration and biological activity.
This paper systematically reviews the chemical structure and physicochemical properties, plant origins and extraction methods, pharmacological activity, mechanism of action and molecular targets, druggability evaluation, and pharmacokinetic characteristics of 4'-demethylated epigmonophyllalxin. Combined with current research progress, it explores its clinical application prospects and future directions, aiming to provide comprehensive and in-depth reference materials for researchers in the field of natural product pharmacology.
4'-Demethylated Epiphytaphyllaxin is a complex organic heterotetracyclic compound with a molecular formula of C22H22O8 and a molecular weight of 400.38. Its structural features include a core backbone of furan naphthalene dioxazohexane, which belongs to phenolic compounds containing multiple hydroxyl and phenolic hydroxyl groups, and possesses high polarity. This compound is the 9-animer isomer of 4'-desmethylophyllodoxin, indicating spatial configuration differences from the parent compound, which may affect its biological activity and pharmacokinetic properties.
In terms of physicochemical parameters, the LogP value of 4'-demethylated podophylloxin is 0.47, indicating strong hydrophilicity, which facilitates distribution in the body but may limit cell membrane penetration. The topological pole surface area (TPSA) is 131.42 Ų, indicating that the molecule has a high number of hydrogen bond acceptors (8), which facilitates stable hydrogen bond interactions with target proteins. Its low blood-brain barrier penetration ability suggests limited distribution in the central nervous system, which helps reduce the risk of CNS toxicity.
Toxicity assessment showed that the compound did not exhibit cardiotoxicity or hERG channel inhibitory activity, reducing the risk of arrhythmias. However, the Ames test was positive, suggesting possible genotoxicity, and its safety evaluation should be prioritized in subsequent drug development.
4'-Demethylated Glyphyllum mainly comes from plants of the genus Podophyllum (Podophyllum spp.), especially Podophyllum hexandrum (Indian Podophyllum hexandrum) and Podophyllum peltatum (American Podophyllum pestatum). These plants are widely used in traditional medicine to treat tumors, inflammation, and viral infections. The Phytophyllum contains abundant epiphylloxin compounds and is an important source of such natural products.
Traditional methods for extracting 4'-demethylphytoxin typically use polar organic solvents such as methanol, ethanol, or ethyl acetate to extract dried plant rhizomes. Subsequently, separation and purification are performed using liquid-liquid partitioning, column chromatography (silica gel column, reversed-phase C18 column), and high-performance liquid chromatography (HPLC). In recent years, the application of modern technologies such as ultrasound-assisted extraction, microwave-assisted extraction, and supercritical fluid extraction has improved extraction efficiency and purity, reducing solvent usage and environmental burden.
The purified 4'-demethylated epiphytaphyllal toxin was confirmed for its structure and purity through multiple analytical methods including mass spectrometry (MS), nuclear magnetic resonance imaging (NMR), and infrared spectroscopy (IR). Due to the low content of this compound in plants, the development of synthetic biology and chemical synthesis methods has also become a research hotspot to meet the needs of large-scale preparation.
The antitumor activity of 4'-desmethylated epiphylloxin is its main pharmacological characteristic. Multiple in vitro cell experiments have shown that this compound has significant proliferation inhibition effects on various tumor cell lines such as lung cancer, breast cancer, colorectal cancer, and leukemia cells. Its half-inhibition concentration (IC50) is usually in the nanomolar to micromolar range, indicating strong cytotoxicity.
Additionally, 4'-demethylated epiophytaxin can induce tumor cell apoptosis and block cell cycle progression, with particularly significant blocking effects during the G2/M phase. Its anti-proliferative effect is also accompanied by activation of cytoskeletal reorganization and DNA damage responses. Some studies suggest that this compound is also effective against multidrug-resistant (MDR) cell lines, suggesting it may bypass traditional resistance mechanisms.
In addition to its antitumor effects, the potential of 4'-desmethylepiepidiphylloxin in antiviral, anti-inflammatory, and immunomodulatory effects has also been gradually discovered. For example, some in vitro experiments have shown that it inhibits the replication of certain viruses, which may be related to its interference with the cell cycle and DNA synthesis.
The antitumor mechanism of 4'-desmethylated epipophyllalis toxin is closely related to its inhibitory effect on DNA topoisomerase II (topoisomerase II). DNA topoisomerase II is an essential enzyme in cellular DNA replication and transcription, capable of regulating the DNA supercoil structure and maintaining genome stability. 4'-Demethylated Epiophylon Toxin stabilizes the compound by binding to the topoisomerase II-DNA complex, blocking the recombination and cleavage cycle of DNA strands, leading to the accumulation of DNA double-strand breaks and inducing apoptosis.
Similar to epipophyllathin, the 9-epitrophic isomer structure of 4'-demethylated epipophyllathathin may affect its binding affinity and selectivity with topoisomerase II. Additionally, this compound may exert anti-tumor effects by regulating cyclein-dependent kinases (CDKs), activating apoptosis-related signaling pathways (such as the caspase family and p53 pathway), and interfering with microtubule dynamics, among other multi-target mechanisms.
Molecular docking and kinetic simulation studies further revealed the binding pattern of 4'-demethylated epipophylloxin to the active site of topoisomerase II, indicating that its hydroxyl and phenolic hydroxyl groups form stable interactions with enzyme active residues via hydrogen bonding, while hydrophobic groups enhance the affinity between the molecule and the enzyme. These molecular-level insights provide a theoretical basis for optimizing its structure to enhance activity and selectivity.
The druggability parameters of 4'-desmethylated dipophylloxin indicate that it has certain potential for drug development. Its lower LogP value (0.47) and higher TPSA (131.42 Ų) suggest strong hydrophilicity, which may affect oral absorption and membrane penetration, but contribute to solubility and distribution in the blood. The blood-brain barrier has low permeability, reducing the risk of central nervous system side effects.
Toxicological evaluation showed that the compound did not exhibit cardiotoxicity or hERG channel inhibition, reducing the safety risk of arrhythmias. However, the positive Ames test suggests possible genotoxicity, which requires special attention during drug development and in-depth genotoxicology and long-term toxicity studies.
In terms of pharmacokinetics, there is currently limited systematic research on 4'-desmethylepiginophyllaxin. It is speculated that it may undergo liver metabolism in the body, with metabolic enzymes mainly including the cytochrome P450 family. Due to its high polarity, rapid renal excretion may occur. In the future, in vivo pharmacokinetic experiments will be needed to clarify its absorption, distribution, metabolism, and excretion (ADME) characteristics, providing a basis for dosage formulation design and administration regimens.
Given the significant antitumor activity and good safety indicators of 4'-desmethylepipophyllaltinoxin in vitro, its potential as a candidate molecule for novel anticancer drugs is worth further exploration. Future research should focus on the following aspects:
Structural optimization and derivative development: Based on molecular docking and pharmacodynamic data, design and synthesize more efficient, selective, and less toxic derivatives to improve pharmacokinetic performance and safety.
In vivo efficacy and safety evaluation: Validation of antitumor activity and toxicological evaluation in animal models to clarify therapeutic window and potential side effects.
Drug combination strategy: Explore the combined use of 4'-desmethylepiophyllodoxin with other chemotherapy drugs, targeted drugs, or immunotherapy drugs, evaluating synergistic effects and overcoming resistance mechanisms.
Formulation development and delivery routes: Developing dosage forms suitable for clinical applications, such as oral formulations, injectables, or nanocarrier systems, to enhance bioavailability and targeting.
Preclinical toxicology and pharmacokinetic research: Systematic studies on genotoxicology, long-term toxicity, and pharmacokinetics, providing safety assurance and dosage guidance for clinical trials.
In summary, 4'-demethylated epiophytaphylloxin, as one of the representative natural antitumor drugs, has promising development prospects. By combining modern drug discovery technologies with precision medicine concepts, it is expected to promote clinical translation.
4'-Demethylated epiodophylloxin, as a natural product with a unique chemical structure and significant antitumor activity, demonstrates vast potential for drug development. Its role in the DNA topoisomerase II inhibitory mechanism provides an important target for anticancer therapy. Although current research on its pharmacokinetics and safety is insufficient, existing druggability evaluations and in vitro pharmacological data provide a solid foundation for subsequent research.
In the future, by integrating modern synthetic chemistry, molecular biology, and pharmacological technologies, in-depth analysis of its mechanism of action, optimization of molecular structure, and improvement of pharmacokinetic characteristics will help promote the clinical application of 4'-demethylated epigduphyllathin and its derivatives, ultimately realizing their value transformation in tumor treatment. As an important research subject in the field of natural product pharmacology, systematic research on 4'-demethylated epipophyllalxin not only enriches the natural anti-cancer drug database but also provides valuable scientific evidence for new drug development.
Shenshuai
Wenjing
Hedandan
