Product name: (Z)-Butylidenephthalide
Synonym name:
Catalogue No.: SBP02864
Cas No.: 72917-31-8
Formula: C₁₂H₁₂O₂
Mol Weight: 188.226
Botanical Source:
Physical Description: Oil
Type of Compound: Miscellaneous

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
The product could be supplied from milligrams to grams. Inquire for bulk scale.
We provide solution to improve the water-solubility of compounds, thereby facilitating the variety of activity tests and clinic uses.

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

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

Introduction/Overview

(Z)-n-butylenephthalein ((Z)-butyllidenephthalidide, CAS No.: 72917-31-8) is a natural γ-lactone compound, structurally belonging to the 2-benzofuran-1(3H)-one derivative. This compound was originally isolated from the traditional Chinese medicinal herb Ligusticum porteri and has recently attracted widespread attention due to its diverse biological activities, especially its hypoglycemic effects. As a natural product, (Z)-n-butenylphthalein not only exhibits significant inhibitory activity on α-glucosidase, but also involves various disease-related molecular targets, covering areas such as pain relief, type 2 diabetes, Alzheimer's disease, liver fibrosis, and tumors. This paper systematically reviews the chemical structure, origins, pharmacological activity, and mechanism of action of (Z)-n-butenylphthalein, combined with druggability evaluation and pharmacokinetic characteristics, to explore its clinical application potential and future development directions.

Chemical structure and physicochemical properties

(Z)-n-butenylphthalein is a natural product with a γ-lactone structure, molecular formula C12H12O2, and molecular weight 188.22. Its structural feature is that the phthalein backbone is replaced by a butyllidene group at 3 positions, forming an alkenyl substituent of the (Z) configuration. This compound belongs to the 2-benzofuran-1(3H)-ketone class, featuring a typical lactone ring structure and aromatic ring system, which gives it good chemical stability and a basis for biological activity.

In terms of physicochemical properties, (Z)-n-butenylphthalein has a LogP value of about 2.95, indicating moderate lipid solubility, which facilitates cell membrane penetration and distribution in vivo. The polar surface area (TPSA) is 34.14 Ų, with 2 hydrogen bond acceptors, suggesting that it may achieve high affinity through limited hydrogen bonding when binding to target proteins. Its molecular structure is compact and possesses excellent blood-brain barrier penetration (high BBB), laying the foundation for its potential applications in central nervous system diseases. Current data have not yet clarified its hepatotoxicity and mutagenicity (Ames test is unknown), but there is no cardiotoxicity or hERG channel inhibition, indicating certain advantages in its safety.

Plant Origins and Extraction Methods

(Z)-n-butene phthalein is mainly isolated from the apiformous plant Ligusticum porteri. Plants of the Ligusticum genus are widely used in traditional Chinese medicine, especially for their remarkable effects in promoting blood circulation and removing blood stasis, analgesic, and anti-inflammatory effects. As one of the important active ingredients in plants of this genus, this compound undertakes some pharmacological effects.

The extraction method typically uses solvent extraction combined with chromatography separation technology. The specific steps include: first, reflux extraction of dried plant rhizomes using ethanol or methanol, concentration followed by silica gel column chromatography separation, combined with high-performance liquid chromatography (HPLC) purification, and finally obtaining high-purity (Z)-n-buteneylphthalein. In recent years, ultrasound-assisted extraction and supercritical CO2 extraction technologies have also been applied to improve extraction efficiency and purity while reducing solvent usage, aligning with the concept of green extraction.

Pharmacological activity research

Blood sugar-lowering effect

(Z)-n-butenylphthalein is best known for its remarkable hypoglycemic effect. In vitro experiments have shown that this compound can effectively inhibit α-glucosidase (EC 3.2.1.20), block the breakdown and absorption of carbohydrates, and delay postprandial blood glucose elevation. Additionally, animal model studies show that it can modulate the insulin signaling pathway, promote the translocation of glucose transporter 4 (GLUT4, SLC2A4) to the cell membrane, enhance tissue glucose uptake, and improve insulin resistance.

Analgesic effect

(Z)-n-butenylphthalein also shows potential value in the field of analgesia. Its targets involve various pain-modulating-related receptors and enzymes, including opioid receptor subtypes such as TRPV1, CNR1 (cannabinoid receptor 1), OPRD1, OPRM1, OPRK1, as well as prostaglandin synthases PTGS1/PTGS2 and TRPA1. Through multi-target regulation, (Z)-n-butenylphthalein can alleviate inflammatory and neuropathic pain, demonstrating a mechanism of action different from traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics.

Neuroprotective and Alzheimer's-related activities

Due to its excellent blood-brain barrier penetration, (Z)-n-butenylphthalein has attracted attention for its use in neurological diseases. Research shows that this compound can inhibit acetylcholinesterase (ACHE) activity, reduce acetylcholine degradation, and improve cognitive function. It also has a certain inhibitory effect on β-secretase 1 (BACE1), which may slow down the formation of β-amyloid protein. Additionally, by modulating abnormal phosphorylation of NMDA receptors and Tau protein, (Z)-n-butenylphthalein demonstrates neuroprotective potential.

Anti-liver fibrosis effect

Liver fibrosis is the common pathological basis for many chronic liver diseases. (Z)-n-butenylphthalein regulates the transforming growth factor β1 (TGFB1), platelet-derived growth factor receptor β (PDGFRB), matrix metalloproteinase 2 (MMP2), and nuclear factor κB (NFKB1) signaling pathways, thereby inhibiting the activation of hepatic stellate cells and excessive collagen deposition, thereby slowing the progression of liver fibrosis.

Antitumor activity

Multiple in vitro and in vivo studies have shown that (Z)-n-butenylphthalein has inhibitory effects on various tumor cells. Its mechanism involves inhibition of cyclin-dependent kinase 1 (CDK1), inducing cell cycle arrest; Regulates the Bcl-2 family proteins to promote tumor cell apoptosis; Inhibiting the NF-κB signaling pathway, reducing inflammation and the supportive role of the tumor microenvironment; and inhibits epidermal growth factor receptor (EGFR) and MAPK signaling pathways, blocking tumor cell proliferation and migration.

Mechanism of action and molecular targets

The multi-target properties of (Z)-n-butenylphthalein form the basis for its multiple pharmacological activities. Its main mechanisms can be summarized as follows:

1. Enzyme inhibition
2. α-Glucosidase (MGAM) inhibition: By competitively inhibiting this enzyme, it reduces carbohydrate hydrolysis and lowers postprandial blood glucose peaks.
3. Acetylcholinesterase (ACHE) inhibition: increases synaptic cleft acetylcholine concentration, improving cognitive function.

4. BACE1 inhibition: slows the production of β-amyloid protein, delaying pathological progression of Alzheimer's disease.

5. receptor regulation

6. TRPV1 and TRPA1 channel regulation: involved in pain signal transduction, alleviating inflammation and neuropathic pain.
7. Opioid receptors (OPRD1, OPRM1, OPRK1) activate: exerts analgesic effects to reduce pain perception.

8. Cannabinoid receptor CNR1 regulation: involved in neuroprotection and analgesia.

9. Signal path regulation

10. NF-κB (NFKB1) inhibition: reduces inflammatory responses and blocks tumor and fibrotic processes.
11. MAPK signaling pathway inhibition: suppresses cell proliferation and tumor development.
12. Cell cycle regulation: inhibits CDK1, inducing tumor cell cycle arrest and apoptosis.

13. Activation of insulin signaling pathways (INSR, SLC2A4, PRKAA1, PPARG): improves insulin sensitivity and promotes glucose metabolism.

14. Gene expression regulation
    By regulating the expression of related genes, it influences cell proliferation, apoptosis, metabolism, and inflammatory responses, demonstrating a wide range of biological effects.

Druggability evaluation and pharmacokinetics

The druggability parameters of (Z)-n-butenylphthalein indicate that it has good potential for drug development. Molecular weight 188.22, LogP 2.95, TPSA 34.14, meeting Lipinski's criteria, indicating good oral bioavailability. Its high lipophilubility and low polarity help it penetrate cell membranes and the blood-brain barrier, making it suitable for treating central nervous system diseases.

Toxicologically, there is currently no clear data on hepatotoxicity or mutagenicity, requiring further systematic evaluation. No cardiotoxicity or hERG channel inhibition, reducing the risk of cardiovascular adverse reactions.

Pharmacokinetic studies show that (Z)-n-butenylphthalein is rapidly absorbed orally and widely distributed in the body, especially at high concentrations in brain tissue. Its metabolic pathway is not fully understood and is presumed to mainly be metabolized through the hepatic enzyme system, requiring further study of its metabolites and excretion methods.

Prospects and outlooks for clinical applications

(Z)-n-butenylphthalein shows broad clinical application prospects due to its multi-target and multi-mechanism pharmacological activity. Its inhibitory effect on α-glucosidase in the treatment of type 2 diabetes provides a natural product candidate for the development of novel hypoglycemic drugs; Its analgesic and neuroprotective properties give it potential in the fields of chronic pain and neurodegenerative diseases such as Alzheimer's disease; Its anti-fibrosis and anti-tumor activities open new directions for the treatment of chronic liver disease and cancer.

Future research should focus on: (1) systematic pharmacokinetic and toxicological evaluation to ensure safety; (2) In-depth analysis of molecular mechanisms to identify key targets and signaling pathways; (3) Optimize extraction and synthesis processes to improve product purity and yield; (4) Conduct preclinical and clinical trials to verify efficacy and safety; (5) Develop structurally modified derivatives to enhance activity and selectivity.

Moreover, combining modern drug design technologies, such as computer-aided drug design (CADD) and multi-omics analysis, will help accelerate the drug development process for (Z)-n-butenylphthalein.

Conclusion

(Z)-n-butenylphthalein, as a natural γ-lactone compound derived from Ligusticum porteri, has become a hot topic in natural product pharmacology research due to its unique chemical structure and diverse biological activities. It demonstrates significant potential in blood sugar lowering, analgesia, neuroprotection, anti-liver fibrosis, and antitumor effects, demonstrating the advantages of natural product multi-target drugs. Although current research on its pharmacokinetics and safety is still incomplete, its favorable druggability parameters lay the foundation for subsequent development. In the future, through systematic pharmacological mechanism analysis and clinical validation, (Z)-n-butenylphthalein is expected to become a novel natural drug for treating various diseases, contributing significantly to the field of natural product pharmacology.