Synonym name: Elatericin A
Catalogue No.: BP0415
Cas No.: 3877-86-9
Formula: C₃₀H₄₄O₇
Mol Weight: 516.675
Botanical Source: plants of the Cucurbitaceae and some others, e.g. Phormium tenax, Sorbaria sorbifolia, Trichosanthes kirilosin, Elaeocarpus glabripetalus, Elaeocarpus hainanensis, Ecballium elaterium, Bryonia spp., Datisca glomerata, Gonystylus keithii a

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 Cucurbitacin D 

NMR of Cucurbitacin D 

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

Introduction/Overview

Cucurbitacin D (CAS No.: 3877-86-9) is a class of tetracyclic triterpene natural products derived from plants in the Cucurbitaceae family. Due to its unique biological activity, it has attracted widespread attention in pharmacology and natural product chemistry. As one of the main active ingredients in Trichosanthes kirilowii (Chuanbei mother gourd), cucurbitacin D not only has significant anti-tumor activity but also demonstrates good anti-inflammatory effects. In recent years, with the development of molecular biology and medicinal chemistry techniques, research on the mechanism of action of cucurbitacin D, its molecular targets, and druggability evaluation has deepened, providing a theoretical foundation and practical guidance for its clinical translation.

This review aims to systematically summarize the chemical structure and physicochemical properties of cucurbitacin D, plant origin and extraction process, pharmacological activity and mechanism of action, druggability evaluation, and pharmacokinetic characteristics, focusing on its potential application value in anti-tumor and anti-inflammatory fields, and looking ahead to its future clinical development prospects.

Chemical structure and physicochemical properties

Cucurbitacin D is a typical member of the cucurbitacin compounds, with a molecular formula C32H44O8 and a molecular weight of 516.6600. Its structural core is a tetracyclic triterpene backbone, containing multiple hydroxyl and ketone groups, giving it high polarity and biological activity. The LogP value of cucurbitacin D is about 3.2, indicating moderate lipid solubility, which facilitates membrane penetration without excessive hydrophobicity that would affect solubility. The polar surface area (TPSA) is 126.79 Ų, and the number of hydrogen bond acceptors is 7, indicating that it exhibits strong hydrogen bond forces when binding to biological macromolecules such as proteins.

Structurally, the polyhydroxyl and ketone structures of cucurbitacin D enable stable binding to various protein targets, especially disruptive interactions with heat shock protein 90 (Hsp90) and its cochaperones Cdc37 and p23, a key feature in its antitumor mechanism. Its blood-brain barrier permeability is relatively low, and hERG channel inhibitory activity is negative, indicating a low risk of cardiotoxicity and certain safety advantages.

Plant Origins and Extraction Methods

Cucurbitacin D is mainly found in the Cucurbitaceae plant Trichosanthes kirilowii, with higher levels in its rhizomes and fruits. Trichosanthes kirilowii, a traditional Chinese medicinal herb, has long been used to clear heat, detoxify, reduce swelling, and relieve pain. Modern research reveals that its abundant cucurbitacin compounds form the basis of its medicinal properties.

Common methods for extracting cucurbitacin D include organic solvent extraction extraction, ultrasound-assisted extraction, and high-performance liquid chromatography (HPLC) separation and purification. Ethanol or methanol is generally used as extraction solvents, and combining ultrasound-assisted extraction technology can improve extraction efficiency. The extract undergoes steps such as concentration, separation, and silica gel column chromatography, and is finally purified by reversed-phase HPLC to obtain high-purity cucurbitacin D.

In recent years, green extraction technologies such as supercritical CO2 extraction and microwave-assisted extraction have also been attempted to extract cucurbitacin D, aiming to increase yield and reduce the use of organic solvents, meeting the environmental and sustainability requirements of modern drug development.

Pharmacological activity research

Antitumor activity

Cucurbitacin D exhibits broad-spectrum anti-tumor activity, covering various solid tumors such as breast, lung, liver, and colorectal cancer. Its antitumor effects mainly manifest as inducing tumor cell cycle blockade, promoting apoptosis, and inhibiting tumor cell migration and invasion capabilities.

Multiple in vitro cell experiments have shown that cucurbitacin D can inhibit tumor cell proliferation by regulating several key signaling pathways. Its induced cell cycle arrest is mostly concentrated in the G2/M phase, accompanied by activation of apoptosis-related proteins, such as cleavage of caspase family members and regulation of Bcl-2 family protein expression. Additionally, cucurbitacin D can downregulate the expression of tumor-related genes such as MCL1 and BCL2, promoting apoptosis.

In vivo models, cucurbitacin D significantly extended survival in tumor model mice by inhibiting tumor growth and metastasis. Its antitumor effect is closely related to its regulation of the tumor microenvironment, including inhibiting the activity of tumor-related matrix metalloproteinase MMP2 and reducing tumor cell invasion and metastasis.

Anti-inflammatory activity

Cucurbitacin D, as an inflammatory body activator, can regulate the inflammatory response of immune cells. By activating the NLRP3 inflammatomer, it induces the release of pro-inflammatory cytokines such as IL-1β and IL-18, thereby participating in the regulation of inflammatory responses. This property gives it potential therapeutic value in certain immune-related diseases.

In addition, cucurbitacin D can exert anti-inflammatory effects by inhibiting the STAT3 signaling pathway, reducing the expression of inflammatory mediators. Its ability to regulate inflammatory responses bidirectionally offers new ideas in the treatment of inflammatory diseases.

Mechanism of action and molecular targets

The pharmacological mechanisms of cucurbitacin D are complex and diverse, mainly realized through the following molecular targets and signaling pathways:

1. Hsp90 and its co-chaperones Cdc37 and p23
   Cucurbitacin D can disrupt the binding of Hsp90 to its helper chaperones Cdc37 and p23, interfering with the function of Hsp90's molecular chaperone function. As a molecular chaperone, Hsp90 maintains the stability and function of various oncoproteins. Its inhibition leads to the degradation of various tumor-associated proteins, suppressing tumor cell growth and survival.

2. STAT3 signaling pathway
   As an important regulatory factor for tumor cell proliferation, survival, and immune evasion, STAT3 D blocks transcriptional activity by inhibiting STAT3 phosphorylation and nuclear translocation, inducing tumor cell apoptosis and suppressing inflammatory responses.

3. Bcl-2 family proteins (MCL1, BCL2)
   Cucurbitacin D regulates the expression of the anti-apoptotic protein Bcl-2 and its homologant MCL1, promoting mitochondrial pathway-mediated apoptosis.

4. Matrix metalloproteinase MMP2
   Inhibits the expression and activity of MMP2, reducing tumor cell invasion and metastasis.

5. DNA topoisomerase TOP1 and TOP2A
   By interfering with DNA topoisomerase activity, cucurbitacin D affects DNA replication and transcription, blocking tumor cell proliferation.

6. HIF1A and MAPK1 signaling pathways
   Inhibits tumor cells' adaptability and cell proliferation signaling in hypoxic environments, enhancing anti-tumor effects.

7. Estrogen receptor ESR1 and aromatase CYP19A1
   In hormone-dependent tumors, cucurbitacin D inhibits tumor growth by regulating ESR1 and CYP19A1 expression, affecting hormone signaling pathways.

In summary, cucurbitacin D demonstrates its antitumor and anti-inflammatory activities through multi-target and multi-pathway synergistic effects, demonstrating its potential as a multifunctional drug molecule.

Druggability evaluation and pharmacokinetics

Druggability evaluation of cucurbitacin D shows it has good potential for drug development. Its molecular weight is 516.66, slightly above the 500 recommended by Lipinski's rules, but still within an acceptable range. The LogP is 3.2, indicating moderate lipid solubility, which is beneficial for oral absorption. TPSA is 126.79 Ų, indicating certain polarity that helps form effective binding with target proteins.

In terms of safety, cucurbitacin D does not inhibit hERG channels, reducing the risk of cardiotoxicity. Its low permeability of the blood-brain barrier may limit the occurrence of central nervous system side effects, but also restrict its application in central nervous system diseases.

Pharmacokinetic studies show that cucurbitacin D has moderate oral bioavailability, is widely distributed in the body, but is mainly concentrated in the liver and kidneys. Its metabolism is mainly carried out through enzymatic reactions in the liver, with most metabolites being hydroxylated and glucuronic acid conjugates. The main excretion routes are bile and urine. Moderate half-life, suitable for daily administration.

Currently, pharmacokinetic data for cucurbitacin D are not yet complete. Further systematic ADME (absorption, distribution, metabolism, excretion) and toxicological studies are needed in the future to improve its druggability evaluation system.

Prospects and outlooks for clinical applications

With its remarkable antitumor and anti-inflammatory activities, Cucurbitacin D shows promising clinical application prospects. Its multi-target mechanism of action gives it potential advantages in treating various tumor types, especially in drug-resistant tumors and multidrug combination therapies.

In the future, cucurbitin D can be used as a monotherapy or combination drug ingredient to develop innovative drugs targeting solid tumors such as breast, lung, and liver cancer. At the same time, its properties as an inflammatory body activator suggest its potential in immune regulation and the treatment of inflammatory diseases, making it worthy of in-depth research in autoimmune diseases, inflammatory bowel disease, and other fields.

However, the clinical translation of cucurbitacin D still faces some challenges, including its low water solubility, limited oral bioavailability, and potential risks of toxic side effects. Therefore, future research should focus on:

• Optimizing drug formulations to improve bioavailability and targeting;
• Improving pharmacokinetic properties through structural modification or nanocarrier technology;
• Systematically assess its safety and efficacy, and conduct preclinical and clinical trials;
• Explore its synergistic mechanisms with existing anticancer drugs to promote combination therapy strategies.

Conclusion

Cucurbitacin D, a natural product derived from Trichosanthes kirilowii, demonstrates broad antitumor and anti-inflammatory potential due to its unique chemical structure and multi-target pharmacological activity. By interfering with the interaction between Hsp90 and cochaper, it regulates key molecules such as STAT3, the Bcl-2 family, and MMP2, exerting cell cycle blocking and apoptosis induction effects, providing new ideas for tumor treatment.

Although druggability evaluations show certain advantages, further improvement in pharmacokinetics and safety data is needed to overcome limitations such as bioavailability and toxicity. In the future, through multidisciplinary collaboration and technological innovation, Cucurbitacin D is expected to become an important candidate molecule in the development of natural product drugs, driving its application in clinical oncology and inflammatory disease treatment.

In summary, cucurbitacin D not only enriches pharmacological research on natural products but also provides a valuable molecular foundation and theoretical support for the development of novel anti-tumor drugs, worthy of ongoing attention and in-depth exploration.