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 '- Demethylpodophyllotoxin (CAS number: 6559-91-7) is an important natural product belonging to the family of organic heterocyclic compounds and is the 9-isomer of 4' - demethylpodophyllotoxin. As a derivative of podophyllotoxin compounds, this compound has received widespread attention due to its significant anti-tumor activity. Podophyllotoxin and its derivatives play an important role in the development of anticancer drugs, and related drugs such as etoposide and teniposide have been successfully applied in clinical treatment of various malignant tumors. The unique chemical configuration and biological activity of 4 '- demethylated podophyllotoxin, as a structural analogue, provide a potential molecular basis for the development of novel anti-tumor drugs.
This article provides a systematic review of the chemical structure and physicochemical properties, plant sources and extraction methods, pharmacological activity, mechanism of action and molecular targets, pharmacological evaluation and pharmacokinetic characteristics of 4 '- demethylated podophyllotoxin. Combined with current research progress, it explores its clinical application prospects and future development directions, aiming to provide comprehensive and in-depth reference materials for researchers in the field of natural product pharmacology.
4 '- demethylated podophyllotoxin is a complex organic heterocyclic compound with a molecular formula of C22H22O8 and a molecular weight of 400.38. Its structural characteristics include a core skeleton of furan naphthalene dioxolane, which belongs to phenolic compounds and contains multiple hydroxyl and phenolic hydroxyl groups, with high polarity. This compound is the 9-isomer of 4 '- demethylated podophyllotoxin, indicating differences in spatial configuration from the parent compound, which may affect its biological activity and pharmacokinetic properties.
In terms of physicochemical parameters, the LogP value of 4 '- demethylated podophyllotoxin is 0.47, indicating its strong hydrophilicity, which is beneficial for in vivo distribution but may limit cell membrane penetration ability. The topological polar surface area (TPSA) is 131.42 Å ², indicating that the molecule has a large number of hydrogen bond acceptors (8), which is conducive to forming stable hydrogen bond interactions with the target protein. Its blood-brain barrier penetration ability is relatively low, indicating limited distribution in the central nervous system, which helps to reduce the risk of central nervous system toxicity.
The toxicity assessment showed that the compound did not exhibit cardiac toxicity or hERG channel inhibitory activity, reducing the risk of arrhythmia. However, the Ames test showed positive, indicating that it may have genotoxicity and requires special attention to its safety evaluation in subsequent drug development.
4 '- demethylated podophyllotoxin mainly comes from plants of the genus Podophyllum spp., especially Podophyllum hexandrum and Podophyllum peltatum in India and America. These plants are widely used in traditional medicine to treat diseases such as tumors, inflammation, and viral infections. Podophyllotoxin compounds are abundant in the plants of Podophyllotoxin, which are an important source of natural products in this class.
The traditional method for extracting 4 '- demethylated podophyllotoxin typically involves extracting dried plant roots and stems using polar organic solvents such as methanol, ethanol, or ethyl acetate. Subsequently, separation and purification were carried out using liquid-liquid partitioning, column chromatography (silica gel column, reverse phase C18 column), and high-performance liquid chromatography (HPLC) techniques. 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, reduced solvent usage and environmental burden.
The structure and purity of the purified 4 '- demethylated podophyllotoxin were confirmed by various analytical methods such as mass spectrometry (MS), nuclear magnetic resonance (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 demand for its large-scale preparation.
The anti-tumor activity of 4 '- demethylated podophyllotoxin is its main pharmacological characteristic. Several in vitro cell experiments have shown that the compound has a significant proliferation inhibitory effect on a variety of tumor cell lines, such as lung cancer, breast cancer, colorectal cancer and leukemia cells. Its half maximal inhibitory concentration (IC50) is typically in the nanomolar to micromolar range, exhibiting strong cytotoxicity.
In addition, 4 '- demethylated podophyllotoxin can induce apoptosis of tumor cells, block cell cycle progression, especially in the G2/M phase where the blocking effect is significant. Its anti proliferative effect is accompanied by the activation of cytoskeleton recombination and DNA damage response. Some studies suggest that the compound is equally effective against multidrug-resistant (MDR) cell lines, suggesting that it may bypass traditional resistance mechanisms.
In addition to its anti-tumor effects, the potential of 4 '- demethylated podophyllotoxin in antiviral, anti-inflammatory, and immune regulation is gradually being discovered. For example, some in vitro experiments have shown that it has inhibitory effects on the replication of certain viruses, which may be related to its interference with the cell cycle and DNA synthesis.
The anti-tumor mechanism of 4 '- demethylated podophyllotoxin is closely related to its inhibitory effect on DNA topoisomerase II. DNA topoisomerase II is an essential enzyme in cellular DNA replication and transcription processes, capable of regulating DNA supercoiled structure and maintaining genomic stability. 4 '- demethylated podophyllotoxin stabilizes the topoisomerase II DNA complex by binding to it, blocking the cycle of DNA strand recombination and breakage, leading to the accumulation of DNA double strand breaks and inducing cell apoptosis.
Similar to podophyllotoxin, the 9-isomer structure of 4 '- demethylated podophyllotoxin may affect its binding affinity and selectivity with topoisomerase II. In addition, the compound may exert anti-tumor effects through multi-target mechanisms such as regulating cyclin dependent kinases (CDKs), activating apoptosis related signaling pathways (such as caspase family, p53 pathway), and interfering with microtubule dynamics.
Molecular docking and dynamic simulation studies further revealed the binding mode between 4 '- demethylated podophyllotoxin and the active site of topoisomerase II, indicating that its hydroxyl and phenolic hydroxyl groups form stable interactions with enzyme active residues through hydrogen bonding, while hydrophobic groups enhance the affinity between the molecule and the enzyme. These molecular level understandings provide a theoretical basis for optimizing their structure to enhance activity and selectivity.
The pharmacological parameters of 4 '- demethylated podophyllotoxin indicate its potential for drug development. Its low LogP value (0.47) and high TPSA (131.42 Å ²) suggest strong hydrophilicity, which may affect oral absorption and cell membrane penetration, but contribute to solubility and distribution in the blood. Low blood-brain barrier permeability reduces the risk of central nervous system side effects.
In toxicology assessment, the compound did not exhibit cardiac toxicity or hERG channel inhibition, reducing the safety risk of arrhythmia. However, the Ames test showed positive, indicating that it may have genetic toxicity, which requires special attention in the drug development process for more in-depth genetic toxicology and long-term toxicity research.
In terms of pharmacokinetics, there is currently limited systematic research on 4 '- demethylated podophyllotoxin. 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, there may be rapid renal excretion. In the future, in vivo pharmacokinetic experiments are needed to clarify its absorption, distribution, metabolism, and excretion (ADME) characteristics, providing a basis for dosage form design and administration regimens.
Given the significant anti-tumor activity and good safety indicators exhibited by 4 '- demethylated podophyllotoxin in vitro, its potential as a candidate molecule for novel anticancer drugs deserves further exploration. Future research should focus on the following aspects:
Structural optimization and derivative development Based on molecular docking and pharmacological data, design and synthesize more efficient, selective, and less toxic derivatives to improve their pharmacokinetic performance and safety.
In vivo efficacy and safety evaluation Conduct anti-tumor activity validation and toxicological evaluation in animal models to clarify their therapeutic window and potential side effects.
Drug combination strategy Explore the combined use of 4 '- demethylated podophyllotoxin with other chemotherapy drugs, targeted drugs, or immunotherapy drugs, evaluate synergistic effects, and overcome resistance mechanisms.
Formulation development and administration route Develop drug delivery formulations suitable for clinical applications, such as oral formulations, injections, or nanocarrier systems, to enhance bioavailability and targeting.
Preclinical toxicology and pharmacokinetic studies The system conducts genetic toxicology, long-term toxicity, and pharmacokinetic studies to provide safety assurance and dosage guidance for clinical trials.
In summary, 4 '- demethylated podophyllotoxin, as one of the representatives of natural anti-tumor drugs, has good development prospects. Combining modern drug discovery technology with precision medicine concepts is expected to promote its clinical translation.
4 '- demethylated podophyllotoxin, as a natural product with unique chemical structure and significant anti-tumor activity, exhibits broad potential for drug development. Its role in the inhibition mechanism of DNA topoisomerase II provides an important target for anti-cancer therapy. Although there is currently insufficient research on its pharmacokinetics and safety, the existing drug efficacy evaluation and in vitro pharmacological data have laid a solid foundation for its subsequent studies.
In the future, combining modern synthetic chemistry, molecular biology, and pharmacology techniques, 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 podophyllotoxin and its derivatives, and ultimately realize its value transformation in tumor treatment. As an important research object in the field of natural product pharmacology, the systematic study of 4 '- demethylated podophyllotoxin not only enriches the natural anti-cancer drug library, but also provides valuable scientific basis for new drug development.
