Synonym name:
Catalogue No.: BP0729
Cas No.: 19202-36-9
Formula: C₃₀H₁₈O₁₀
Mol Weight: 538.464
Botanical Source: Obt. from leaves of Chamaecyparis obtusa. Also from Psilotum triquetrum. Present in the Cupressaceae, Cycadales and many other plants

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:

Hinokiflavone has significant cytotoxicity, it has inhibition of MMP-9.

References:

Planta Med. 1989 Apr;55(2):166-8.    

Hinokiflavone, a cytotoxic principle from Rhus succedanea and the cytotoxicity of the related biflavonoids.   

Hinokiflavone (1) was isolated as the cytotoxic principle from the drupes of Rhus succedanea L. 

METHODS AND RESULTS:

A comparison of the cytotoxicity of 1 and other related biflavonoids, including amentoflavone (2), robustaflavone (3), agathisflavone (4), rhusflavone (5), rhusflavanone (6) and its hexaacetate (7), succedaneaflavanone (8) and its hexaacetate (9), cupressuflavone (10), neorhusflavanone (11), volkensiflavone (12) and its hexamethyl ether (13), spicataside (14) and its nonaacetate (15), morelloflavone (16) and its heptaacetate (17) and heptamethyl ether (18), GB-1a (19) and its hexamethyl ether (20) and 7"-O-beta-glucoside (21), and GB-2a (22), indicates that an ether linkage between two units of apigenin as seen in 1 is structurally required for significant cytotoxicity. Compounds 13 and 20 also demonstrated significant cytotoxicity.    

HPLC of Hinokiflavone

NMR of Hinokiflavone

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

Introduction/Overview

Natural products have always been an important source of innovative drug discovery, among which flavonoids have attracted much attention due to their wide range of biological activities. Hinokiflavone, CAS number 19202-36-9, as a unique flavonoid compound, has gradually become a hot topic in pharmacological research in recent years due to its novel mechanism of action and diverse pharmacological activities. Early research mainly focused on its traditional flavonoid activities such as anti-inflammatory and antioxidant effects, while studies in the past decade have revealed its key roles in regulating pre mRNA splicing, inhibiting matrix metalloproteinases (MMPs), regulating protein SUMOylation modifications, and inducing tumor cell apoptosis. Especially in the fields of breast cancer, virus infection and bacterial drug resistance, Platycladus obtusifolia biflavone shows the potential of multi target and multi pathway intervention, providing a lead compound for the development of new therapeutic strategies. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, and medicinal properties of Platycodon grandiflorus flavonoids, and to explore their clinical application prospects.

Chemical structure and physicochemical properties

Platycodon grandiflorus is a type of flavonoid compound composed of two flavonoid units connected by C-O-C ether bonds. Its molecular formula is C30H18O10 and its molecular weight is 538.4640. Its basic skeleton is composed of two apigenin or its derivative units, and this unique dimeric structure is the chemical basis that distinguishes it from flavonoids and produces special biological activities.

In terms of physicochemical properties, the lipid water partition coefficient (LogP) of Platycodon grandiflorus is 3.9234, indicating its moderate lipophilicity. Its topological polar surface area (TPSA) is 170.8000 Å ², reflecting the presence of multiple polar oxygen atoms (such as hydroxyl, carbonyl, and ether bonds) in the molecule. These parameters collectively determine its extremely low water solubility, approximately 0.0001 mg/mL, which poses a challenge for its formulation development. Preliminary pharmacological predictions indicate that its ability to cross the blood-brain barrier is low, suggesting that it may not be suitable for direct treatment of central nervous system diseases. In the preliminary safety screening, the compound did not show significant hERG potassium channel inhibitory activity (low risk of arrhythmia), and the Ames test result was 0.6, indicating that its mutagenic risk is low and has a preliminary safety basis for further development.

Plant sources and extraction methods

The biflavones of Platycladus orientalis mainly exist in the Cupressaceae and Arhat plants. Its name "Hinokiflavone" is derived from Chamaecyparis obtusa (Hinoki in Japanese). In addition, it has also been found in Platycladus orientalis, Juniperus spp., and some Selaginella plants. It is usually produced as a secondary metabolite in plants and may participate in plant defense responses.

Organic solvent extraction is commonly used to extract dihydroketone from plant materials. The classic process includes: reflux extraction or ultrasound assisted extraction of dried and crushed plant materials (such as branches and leaves) using methanol or ethanol. After vacuum concentration, the crude extract was subjected to gradient extraction using solvents such as petroleum ether and ethyl acetate. The flavonoids in Platycodon grandiflorus were mainly enriched in the ethyl acetate fraction. Further purification depends on various chromatographic techniques, such as silica gel column chromatography, Sephadex LH-20 column chromatography and high performance liquid chromatography (HPLC). In recent years, green extraction techniques such as supercritical fluid extraction have also been explored to improve extraction efficiency and selectivity. The extraction rate is influenced by various factors such as plant variety, location, harvest season, and extraction process.

Pharmacological activity research

Numerous in vitro and in vivo studies have confirmed that flavonoids from Platycodon grandiflorus have a wide range of pharmacological activities, mainly including the following aspects:

1. Antitumor activity The flavonoids of Platycladus orientalis showed significant inhibitory activity on a variety of tumor cells, especially in the study of breast cancer. It can effectively inhibit the proliferation, migration and invasion of breast cancer cells. Its anti-tumor effect is related to inducing cell cycle arrest, promoting cell apoptosis, and inhibiting metastasis.
2. Anti inflammatory and immune regulatory activity Platycodon grandiflorus can inhibit the production of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines (such as TNF - α, IL-6) in macrophages induced by lipopolysaccharides (LPS), and its effect is related to the inhibition of inflammatory signaling pathways such as NF - κ B.
3. Antiviral activity Research has shown that flavonoids from Platycodon grandiflorus have certain inhibitory effects on human immunodeficiency virus (HIV), hepatitis B virus (HBV), and herpes simplex virus (HSV). Its antiviral mechanism may be related to interfering with the virus replication cycle or regulating host cell responses.
4. Antibacterial and antiviral activity An important discovery is that Platycodon grandiflorus can effectively inhibit the virulence of methicillin-resistant Staphylococcus aureus (MRSA). Its function is not to directly kill bacteria, but to weaken the pathogenic ability of bacteria by inhibiting their casein lyase P (ClpP), providing a new "anti virulence" strategy for addressing bacterial resistance.
5. Enzyme inhibitory activity Platycodon grandiflorus is an effective inhibitor of matrix metalloproteinases (MMPs, such as MMP2), which is directly related to its anti-tumor invasion and metastasis activity. Meanwhile, it has also been identified as a SUMO specific protease 1 (SENP1) inhibitor, which can interfere with the SUMO modification process of intracellular proteins.

Mechanism of action and molecular targets

The multiple pharmacological activities of Platycodon grandiflorus flavonoids stem from their intervention in multiple key targets and pathways in cells, forming a multi-target action network.

• Regulating pre mRNA splicing Bianbai flavonoids have been identified as a novel precursor mRNA splicing regulator. It can affect the production of splicing isoforms of specific genes, thereby altering the expression profile of functional proteins, which has potential significance in cancer treatment as splicing abnormalities are a hallmark of tumors.
• Inducing cell apoptosis and autophagy In breast cancer and other tumor cells, flavonoids from Platycladus obtusifolia induce apoptosis through the endogenous mitochondrial pathway. The mechanism involves:1) Activate AMPK (PRKAA1) signaling pathway Regulating cellular energy metabolism and growth;2) Downregulate the expression of anti apoptotic protein Bcl-2 (BCL2)Disrupting mitochondrial membrane potential;3) Inhibition of transcription factor STAT3 (STAT3) activation Thereby downregulating downstream survival genes;4) Promote excessive production of reactive oxygen species (ROS)Leading to oxidative stress and mitochondrial damage.
• Inhibit tumor metastasis This function is mainly achieved through Inhibition of the activity and expression of matrix metalloproteinases MMP2 and MMP9 To achieve. MMPs are key enzymes that degrade the extracellular matrix, and inhibition of their activity can effectively block the invasion and metastasis of tumor cells.
• Affects hormone and drug resistance related targets Research has shown that flavonoids from Platycodon grandiflorus can interact with estrogen receptor beta (ESR2) and may produce selective estrogen receptor regulatory effects. In addition, it can also down regulate or inhibit the function of tumor multidrug resistance proteins such as P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), which is expected to reverse the chemotherapy resistance of tumor cells.
• Inhibition of SUMOylation modification pathway As a SENP1 inhibitor, Platycodon grandiflorus inhibits the removal of SUMO protein from substrate protein (de SUMO). SUMOylation is an important post-translational modification of proteins involved in regulating transcription, DNA repair, cell cycle, and other processes. Its dysregulation is closely related to the occurrence and development of tumors. Inhibition of SENP1 can lead to abnormal SUMOylation levels of specific target proteins, such as certain tumor suppressor factors or oncogenes, thereby affecting their function and stability.
• Other targets The study also suggests that flavonoids from Platycodon grandiflorus may have an impact on protein kinase C alpha (PRKCA), microtubule associated protein tau (MAPT), and other targets that are associated with cell signal transduction and neurodegenerative diseases, expanding their potential applications.

Evaluation of drug properties and pharmacokinetics

Although the pharmacological activity of Platycodon grandiflorus is significant, its medicinal properties still face challenges, and related research is still in the preclinical stage.

• Absorption, distribution, metabolism, excretion (ADME)Due to its extremely low water solubility, the oral bioavailability of Platycodon grandiflorus may be limited. A moderate LogP value suggests that it has a certain degree of membrane permeability. At present, there is a lack of publicly available pharmacokinetic data in vivo. Its metabolic pathway may be similar to other flavonoids, undergoing extensive II binding reactions in the liver (such as glucuronidation and sulfation) and excreted through bile or urine.
• Formulation Challenge To improve its bioavailability, it is necessary to develop suitable drug delivery systems. Formulation strategies such as nanocrystal technology, liposomes, micelles, or solid dispersions may be used to improve their solubility and dissolution rate.
• Preliminary Safety Assessment The existing preliminary toxicological data (such as no hERG inhibition and negative Ames test) provide first-line support for its safety. However, comprehensive evaluations of acute toxicity, long-term toxicity, and reproductive toxicity still need to be conducted in the future.
• Potential for drug interactions As a flavonoid compound, it may affect the metabolism of other co administered drugs by inhibiting or inducing cytochrome P450 enzyme systems (such as CYP3A4), which is a closely monitored issue in subsequent development.

Clinical application prospects and prospects

As a multi-target natural product, Platycodon grandiflorus has broad clinical application prospects, but the transformation path still needs further exploration.

1. Antitumor therapy, especially breast cancer: It inhibits tumor growth and metastasis through multiple pathways such as AMPK/STAT3/BCL2/MMPs, and has the potential to reverse drug resistance, making it hopeful to become a candidate drug for adjuvant treatment or combination of drugs for breast cancer. The value of triple negative breast cancer and other refractory subtypes deserves further study.
2. Antimicrobial agents with anti toxicity properties The strategy of reducing MRSA virulence by inhibiting ClpP instead of directly killing bacteria is less likely to trigger strong bacterial resistance selection pressure, providing new ideas for addressing the global antibiotic resistance crisis.
3. Antiviral and anti-inflammatory applications Its antiviral and anti-inflammatory activities provide the possibility for developing drugs to treat chronic viral infections (such as HBV) or inflammation related diseases (such as arthritis).
4. Combination therapy strategy Given its multi-target nature, the combination of Platycodon grandiflorus flavonoids with existing chemotherapy drugs, targeted drugs, or immune checkpoint inhibitors may produce synergistic effects, reduce drug dosage, and overcome drug resistance.
5. Future research directions and challenges：
   • Deep exploration of mechanisms Further clarification is needed on its specific downstream effect network and disease specificity as a splicing regulator and SENP1 inhibitor.
   • structural optimization Based on its pharmacophore, reasonable structural modifications are carried out to improve water solubility, metabolic stability, and target selectivity, reducing potential off target effects.
   • Advanced delivery system development Effective nanomedicine or prodrug strategies must be developed to address the core bottleneck of drug development.
   • Preclinical and clinical research Completing standardized preclinical pharmacological, pharmacokinetic, and toxicological evaluations of the system is a necessary step towards advancing it towards clinical trials.

Conclusion

Platycodon grandiflorus is a unique plant derived flavonoid compound, whose value has surpassed the traditional antioxidant category. Modern pharmacological research has revealed its strong potential as a multi-target regulator, particularly playing an important role in regulating cutting-edge biological processes such as RNA splicing, protein SUMOylation modification, inducing tumor cell apoptosis, inhibiting transferases, and implementing "anti toxicity" antibacterial measures. Despite facing challenges in solubility and systemic pharmacokinetics, its rich pharmacological activity and novel mechanism of action make it an attractive drug lead compound and molecular probe. With a deeper understanding of the mechanism of action, rational modification of medicinal chemistry, and the application of new delivery technologies, Platycodon grandiflorus is expected to provide new weapons for the treatment of major diseases such as tumors and drug-resistant bacterial infections in the future, demonstrating the long-lasting vitality of natural products in innovative drug development.