Pharmacological research progress of sulforetin: from natural products to potential therapeutic drugs
Introduction/Overview
Natural products, as an important source of drug discovery, have long played an irreplaceable role in maintaining human health and treating diseases. Among numerous natural compounds with biological activity, sulforetin (CAS number: 120-05-8), as an important flavonoid compound, has attracted widespread attention from pharmacological researchers in recent years. Sulfur yellow chrysanthemum belongs to aurone compounds, and its unique chemical structure and diverse biological activities make it a research hotspot in the field of natural product pharmacology.
Sulfur yellow chrysanthemum was originally isolated from Asteraceae plants, and its name comes from its discovery source - sulfur yellow chrysanthemum（Cosmos sulphureus）. With the deepening of research, scientists have found that sulfur yellow chrysanthemum is not only present in Asteraceae plants, but also widely distributed in various medicinal plants. This compound exhibits significant anti-inflammatory, antioxidant, antiplatelet aggregation, and anti mutagenic activities, particularly in inhibiting the nuclear factor kappa B (NF - κ B) signaling pathway, demonstrating a unique mechanism of action. In addition, as a competitive inhibitor of tyrosinase (TYR), thiocyanate has inhibitory effects on both monophenolase and diphenolase activities, with an IC50 value of 13.64 μ M. This characteristic makes it potentially valuable for the treatment of skin whitening and pigmentation diseases.
In recent years, significant progress has been made in the research of sulforaphane in the fields of allergic airway inflammation, oxidative stress-related diseases, and cardiovascular diseases related to platelet aggregation. This article aims to systematically review the chemical structure, plant origin, pharmacological activity, mechanism of action, pharmacological evaluation, and clinical application prospects of sulforaphane, in order to provide comprehensive references for further research and development of this natural product.
Chemical structure and physicochemical properties
Chemical structural characteristics
Sulfur yellow chrysanthemum belongs to orange ketone compounds, and its basic skeleton is a benzofuranone structure. From a chemical structure perspective, thiocyanate (chemical name: 2-phenylmethylene-6-hydroxy-3 (2H) - benzofuranone) has a typical orange ketone core, consisting of a benzofuranone ring and a benzyl side chain. Its molecular formula is C15H10O5 and its molecular weight is 270.2400 Da. The structure contains an alpha, beta unsaturated ketone system, which is closely related to its various biological activities.
There are multiple hydroxyl groups in the chemical structure of sulfur yellow chrysanthemum extract, which not only affect its solubility and chemical reactivity, but also serve as the key structural basis for its antioxidant activity. Specifically, sulfur yellow chrysanthemum contains hydroxyl substituents on the A and B rings, which can provide hydrogen atoms to scavenge free radicals and exert antioxidant effects.
Physical and chemical property parameters
According to the analysis of medicinal chemical properties, sulfocyanine exhibits the following important physicochemical properties:
Lipid water partition coefficient (LogP)The LogP value of thiocyanate is 2.6844, indicating that the compound has moderate lipid solubility. This characteristic enables it to have a certain degree of permeability in biological membranes while maintaining a certain degree of water solubility, which is beneficial for its distribution and transport in the body.
Topological Polarity Surface Area (TPSA)The TPSA value is 86.9900 Å ², which reflects the polarity characteristics of the compound. According to the empirical rules of medicinal chemistry, compounds with a TPSA less than 140 Å ² typically have good oral bioavailability, and the TPSA value of thiocyanate meets this standard, indicating its good oral absorption potential.
Water solubility The water solubility of thiocyanate is 0.0648 mg/mL, which belongs to low water solubility compounds. This characteristic may limit its in vivo absorption and bioavailability, and needs to be improved through appropriate drug delivery systems or structural modifications.
Blood-brain barrier permeability The evaluation results show that the blood-brain barrier permeability of sulforaphane is low, which means that the distribution of this compound in the central nervous system is limited. This characteristic may be advantageous for therapeutic applications that require targeting peripheral targets, as it can reduce the risk of central nervous system related side effects.
HERG inhibition Sulfur yellow chrysanthemum extract has no inhibitory activity on hERG potassium channels, indicating a low risk of cardiac toxicity, which is an important safety indicator in drug development.
Ames test The Ames test result is 1.2, indicating that sulforaphane exhibits weak or suspected positivity in bacterial reverse mutation assays, suggesting a potential genetic toxicity risk. This finding needs further validation and evaluation in subsequent studies.
Plant sources and extraction methods
Plant-based
Sulfur yellow chrysanthemum extract is widely distributed in nature, mainly found in the flowers, leaves, and roots of Asteraceae plants. The following are the main plant sources reported to contain thiocyanate:
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Sulfur yellow chrysanthemum（Cosmos sulphureus）As the source plant for the naming of sulfur yellow chrysanthemum, sulfur yellow chrysanthemum is rich in this compound in its petals and is the most commonly used extraction material in research.
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Calendula flower（Calendula officinalis）The inflorescence of marigold contains various flavonoids, among which sulfur yellow chrysanthemum is one of the important components.
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Chrysanthemum（Chrysanthemum morifolium）The presence of thiocyanate was detected in the petals of traditional medicinal plant chrysanthemum, which may be related to the anti-inflammatory and antioxidant effects of chrysanthemum.
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Dandelion（Taraxacum officinale）Dandelion roots and leaves contain sulfocyanin, which may be involved in its anti-inflammatory and diuretic effects.
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Purple cone chrysanthemum（Echinacea purpurea）The aboveground part of Echinochloa purpurea contains sulfocyanins, which may be related to its immunomodulatory activity.
In addition, sulforaphane has also been found in some other families and genera of plants, such as certain species in leguminous plants. The content of thiocyanate varies greatly among different plant sources, usually influenced by factors such as plant variety, growth environment, harvest season, and processing methods.
extraction method
The extraction methods of thiocyanate mainly include traditional solvent extraction and modern assisted extraction techniques:
Traditional solvent extraction method：
- Ethanol extraction method Ethanol of different concentrations (usually 50% -95%) is used as a solvent to extract thiocyanate from plant materials through cold soaking, percolation, or reflux extraction methods. This method is easy to operate and cost-effective, but the extraction efficiency is affected by factors such as temperature, time, and solvent ratio.
- Methanol extraction method Methanol has good solubility for sulfur yellow chrysanthemum extract and is often used as the preferred solvent for laboratory research. However, the toxicity of methanol limits its application in food and pharmaceutical production.
Modern assisted extraction technology：
- Ultrasound assisted extraction Utilizing the cavitation effect of ultrasound to destroy plant cell walls and improve the dissolution efficiency of sulforaphane. This method has the advantages of short extraction time, low solvent dosage, and high extraction rate.
- Microwave assisted extraction Using microwave radiation to rapidly increase the internal temperature of plant tissues and accelerate the release of target compounds. This method is suitable for compounds with good thermal stability.
- Supercritical fluid extraction Selective extraction is achieved by adjusting pressure and temperature using supercritical CO2 as the solvent. This method is green and environmentally friendly, with no solvent residue, but the equipment cost is relatively high.
Purification Method：
After extraction, the purification of endospermethrin usually uses column chromatography technology, including silica gel column chromatography, polyamide column chromatography, Sephadex LH-20 gel column chromatography and high performance liquid chromatography (HPLC). In recent years, high-speed counter current chromatography (HSCCC) and preparative HPLC have also been applied for the efficient purification of thiocyanate.
Pharmacological activity research
anti-inflammatory activity
The anti-inflammatory activity of sulfur yellow chrysanthemum extract is one of its most concerned pharmacological effects. Research has shown that sulfur yellow chrysanthemum extract can significantly inhibit the production and release of various inflammatory mediators. In a macrophage model stimulated by lipopolysaccharide (LPS), sulforaphane dose dependently inhibits the production of pro-inflammatory factors such as nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor - α (TNF - α), interleukin-6 (IL-6), and interleukin-1 β (IL-1 β).
Of particular note is the significant therapeutic effect of thiocyanate in allergic airway inflammation models. By inhibiting the activation of the NF - κ B pathway, thiocyanate can alleviate airway inflammation, reduce eosinophil infiltration, decrease mucus secretion, and improve airway hyperresponsiveness. This discovery suggests that sulforaphane may become a novel candidate drug for treating allergic respiratory diseases such as asthma.
antioxidant activity
Sulfur yellow chrysanthemum extract exhibits strong antioxidant capacity, and its antioxidant mechanism involves multiple levels. Firstly, the phenolic hydroxyl group in the molecule of sulfur yellow chrysanthemum can directly scavenge free radicals, including hydroxyl radicals (· OH), superoxide anion radicals (O2 · -), and hydrogen peroxide (H2O2). Secondly, thiocyanate can activate the nuclear factor E2 related factor 2 (NRF2/NFE2L2) signaling pathway and upregulate the expression of a series of antioxidant enzymes, including superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), catalase (CAT), glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (HMOX1).
In addition, sulfur yellow chrysanthemum extract can also inhibit the activity of matrix metalloproteinase 1 (MMP1) and matrix metalloproteinase 3 (MMP3), which play important roles in oxidative stress-related tissue damage and remodeling processes. By regulating the antioxidant enzyme system and inhibiting tissue damage induced by oxidative stress, thiocyanate has shown protective effects in various oxidative stress-related disease models.
Antiplatelet aggregation activity
Platelet aggregation plays a crucial role in thrombosis and the occurrence and development of cardiovascular diseases. Research has found that sulfur yellow chrysanthemum extract can effectively inhibit platelet aggregation, and its mechanism of action may be related to inhibiting the activation of signaling pathways during platelet activation. Thioflavin inhibits platelet aggregation by suppressing the increase in calcium ion concentration and the production of thromboxane A2 (TXA2) in platelets.
Compared with traditional antiplatelet drugs, the antiplatelet activity of thiocyanate has the characteristics of mild action and fewer side effects, which makes it potentially advantageous in the prevention and treatment of thrombotic diseases.
Tyrosinase inhibitory activity
As a competitive tyrosinase inhibitor, thiocyanate exhibits inhibitory effects on both monophenolase and diphenolase activities, with an IC50 value of 13.64 μ M. Tyrosinase is a key rate limiting enzyme in the process of melanin synthesis, and abnormal increase in its activity can lead to pigmentation disorders such as melasma, freckles, and age spots.
The study on the inhibitory mechanism of sulfur yellow chrysanthemum on tyrosinase shows that this compound can bind to the active center of tyrosinase and competitively inhibit the conversion of substrates (tyrosine and dopa). This characteristic makes sulforaphane a candidate compound for the development of new skin whitening agents and treatment drugs for pigmentation diseases.
Anti mutagenic activity
Sulfur yellow chrysanthemum extract also exhibits certain anti mutagenic activity. Research has shown that sulfur yellow chrysanthemum extract can reduce the frequency of gene mutations induced by chemical mutagens, and its anti mutagenic mechanism may involve protective effects against DNA damage and enhanced DNA repair ability. However, it is worth noting that the Ames test results showed a weak positive reaction for sulforaphane, suggesting its potential genetic toxicity. This contradictory phenomenon requires further in-depth research.
Mechanism of action and molecular targets
Inhibition of NF - κ B signaling pathway
The core mechanism of the anti-inflammatory activity of thiocyanate lies in its inhibition of the NF - κ B signaling pathway. NF - κ B is an important transcription factor that regulates the expression of various inflammation related genes. In the resting state, NF - κ B binds to the inhibitory protein I κ B and exists in an inactive form in the cytoplasm. When cells are stimulated by inflammation (such as LPS, TNF - α, etc.), I κ B kinase (IKK) is activated, phosphorylating I κ B protein, leading to its ubiquitination degradation, releasing NF - κ B into the nucleus, and initiating transcription of target genes.
Thioflavin inhibits the activity of IKK, preventing the phosphorylation and degradation of I κ B, thereby blocking the nuclear translocation and transcriptional activation of NF - κ B. In addition, sulfur yellow chrysanthemum extract can directly inhibit the binding ability of NF - κ B to DNA, further weakening its transcriptional activity. By inhibiting the NF - κ B pathway, thiocyanate downregulates the expression of various inflammatory mediators such as TNF - α, IL-6, IL-1 β, COX-2, and iNOS, exerting anti-inflammatory effects.
Activation of NRF2/ARE signaling pathway
The antioxidant activity of thiocyanate is mainly achieved by activating the NRF2/ARE signaling pathway. NRF2 (encoded by NFE2L2 gene) is an alkaline leucine zipper transcription factor that is a key regulator of cellular antioxidant defense system. Under normal conditions, NRF2 binds to Kelch like ECH related protein 1 (KEAP1) and is degraded by ubiquitination. When cells are exposed to oxidative stress or electrophilic agents, NRF2 is released from KEAP1, transferred to the nucleus, binds to antioxidant response elements (ARE), and initiates transcription of a series of antioxidant and detoxifying enzyme genes.
Sulfur yellow chrysanthemum extract can promote nuclear translocation of NRF2, enhance its binding activity with ARE, and upregulate the expression of antioxidant enzymes such as SOD1, SOD2, CAT, GPX1, and HMOX1. These enzymes work together to clear reactive oxygen species (ROS), maintain intracellular redox balance, and protect cells from oxidative damage.
Inhibition of Tyrosinase Activity
The inhibitory effect of thiocyanate on tyrosinase is an important mechanism of its use as a skin whitening agent. Tyrosinase is a copper containing oxidase that catalyzes two key reactions in melanin synthesis: tyrosine hydroxylation to dopa (monophenolase activity) and dopa oxidation to dopa quinone (diphenolase activity).
Dynamics studies have shown that sulforaphane is a competitive inhibitor of tyrosinase, with an IC50 value of 13.64 μ M. Molecular docking analysis shows that sulfur yellow chrysanthemum can form coordination bonds with copper ions in the active center of tyrosinase, and bind to amino acid residues of the enzyme protein through hydrogen bonding and hydrophobic interactions, occupying the binding site of the substrate and inhibiting the catalytic activity of the enzyme.
Other molecular targets
In addition to the main targets mentioned above, thiocyanate also exerts pharmacological effects by regulating other molecular targets:
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Inhibition of MMP1 and MMP3 Sulfur yellow chrysanthemum extract can inhibit the activity of matrix metalloproteinases MMP1 and MMP3, which are involved in the degradation of extracellular matrix and tissue remodeling, and play important roles in inflammation, tumor invasion, and skin aging.
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SOD1 and SOD2 regulation Thioflavin upregulates the expression of superoxide dismutase SOD1 and SOD2, enhances the ability of cells to clear superoxide anions, and reduces oxidative stress damage.
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HMOX1 induction Thioflavin induces the expression of heme oxygenase 1 (HMOX1), which catalyzes the degradation of heme into biliverdin, carbon monoxide, and iron ions. These products have anti-inflammatory, antioxidant, and cell protective effects.
Evaluation of drug properties and pharmacokinetics
Drugability assessment
Based on medicinal chemistry and pharmacological parameters, the pharmacological properties of sulforaphane can be evaluated from the following aspects:
Analysis of drug properties According to Lipinski's "Rule of Five", the molecular weight (270.24 Da) of thiocyanate is less than 500, the LogP value (2.68) is less than 5, the number of hydrogen bond donors (phenolic hydroxyl groups) is 3, and the number of hydrogen bond acceptors is 5, which meets the basic requirements of drug like compounds. The TPSA value (86.99 Å ²) is also within the ideal range, indicating its good oral absorption potential.
safety assessment A negative hERG inhibition test indicates a low risk of cardiac toxicity for sulfocyanine. However, the weak positive results of the Ames test should be taken seriously, indicating that the compound may pose a risk of genetic toxicity. This discovery needs to be further validated in in vivo experiments and preclinical safety evaluations. In addition, the toxic effects of thiocyanate on normal cells also need to be systematically evaluated.
Metabolic stability As a flavonoid compound, thiocyanate may undergo extensive phase II metabolism in the body, including glucuronidation, sulfation, and methylation reactions. These metabolic processes may affect their bioavailability and pharmacological activity. At present, there is insufficient research on the metabolic stability of thiocyanate, and further metabolomics and pharmacokinetic studies are needed.
Pharmacokinetic characteristics
The pharmacokinetic study of thiocyanate is still in its preliminary stage, and the existing data mainly comes from animal experiments and in vitro studies
absorb The oral absorption of thiocyanate may be limited by its low water solubility. The LogP value is 2.68, indicating that it has moderate lipid solubility and theoretically can penetrate intestinal epithelial cells through passive diffusion. However, low water solubility may lead to slow dissolution rate and affect oral bioavailability. The use of formulation techniques such as solid dispersions, lipid nanoparticles, or cyclodextrin inclusion complexes may improve their oral absorption.
distribution The low blood-brain barrier permeability of thiocyanate suggests limited distribution in the central nervous system. This characteristic may be beneficial for treating peripheral inflammation and oxidative stress-related diseases, reducing the risk of central nervous system side effects. Further research is needed to determine the distribution volume and tissue affinity of thiocyanate in vivo.
Metabolism As a polyphenolic compound, thiocyanate may undergo extensive phase II metabolism in the liver and intestines. The main metabolic pathways include glucuronic acid binding, sulfate binding, and methylation modification. These metabolites may retain some pharmacological activity or be rapidly cleared. The phase I metabolism mediated by cytochrome P450 enzymes may not be the main metabolic pathway of sulforaphane.
excretion Sulfur yellow chrysanthemum extract and its metabolites may be mainly excreted through bile and urine. Due to the increased water solubility of phase II metabolites, they are beneficial for excretion through the kidneys. Further pharmacokinetic studies are needed to determine the specific excretion pathways and clearance rates.
Clinical application prospects and prospects
Potential therapeutic areas
Based on the pharmacological activity spectrum of sulfur yellow chrysanthemum extract, it has potential application prospects in the following disease fields:
allergic airway inflammation Sulfur yellow chrysanthemum extract has shown significant therapeutic effects in allergic airway inflammation models by inhibiting the NF - κ B pathway and regulating immune responses. This provides candidate compounds for the development of new drugs for the treatment of respiratory diseases such as asthma and allergic rhinitis.
Oxidative stress-related diseases The strong antioxidant activity of endosperm and its activation of NRF2 pathway make it potentially useful in the treatment of oxidative stress related diseases (such as neurodegenerative diseases, cardiovascular diseases, diabetes complications and aging related diseases).
Pigmentation related diseases As a tyrosinase inhibitor, thiocyanate can be used to develop drugs or cosmetic ingredients for the treatment of pigmentation diseases such as melasma, freckles, and age spots. Its competitive inhibition mechanism and moderate IC50 value make it a promising skin whitening agent.
Thrombotic disease The antiplatelet aggregation activity of thiocyanate suggests its potential application value in the prevention and treatment of thrombotic diseases such as myocardial infarction, stroke, and deep vein thrombosis.
Research Challenges and Future Directions
Despite exhibiting various pharmacological activities, the clinical translation of thiocyanate still faces many challenges
The issue of bioavailability The low water solubility and potential widespread first pass metabolism of thiocyanate limit its oral bioavailability. Future research requires the development of suitable drug delivery systems, such as nanomaterials, liposomes, phospholipid complexes, etc., to enhance their bioavailability.
safety assessment The weak positive results of the Ames test suggest that sulfocyanine may pose a genetic toxicity risk and require a more comprehensive toxicological evaluation, including in vivo micronucleus testing, chromosome aberration testing, and long-term toxicity studies.
structural optimization Based on the chemical structure of thiocyanate, reasonable structural modifications such as introducing hydrophilic groups, changing the hydroxyl substitution mode, or synthesizing derivatives may improve its pharmacokinetic properties and pharmacological activity.
In depth study of the mechanism of action Although the role of thiocyanate in the NF - κ B and NRF2 pathways has been preliminarily understood, the details of its interactions with key proteins in these signaling pathways still need further clarification. In addition, it is also worth exploring whether sulforaphane acts on other unknown targets.
preclinical research Before entering clinical trials, it is necessary to conduct systematic pharmacokinetic, pharmacodynamic, and toxicological studies, establish appropriate animal models, and evaluate the therapeutic index and safety window of sulfamethoxazole.
Conclusion
As a natural orange ketone compound with a unique chemical structure, thiocyanate exhibits various pharmacological activities such as anti-inflammatory, antioxidant, antiplatelet aggregation, and tyrosinase inhibition. It exerts biological effects by inhibiting the NF - κ B pathway, activating the NRF2/ARE signaling pathway, and competitively inhibiting tyrosinase, and has potential application value in the treatment of allergic airway inflammation, oxidative stress-related diseases, and pigmentation diseases.
However, the clinical translation of thiocyanate still faces challenges such as low bioavailability and potential genotoxicity. Future research requires continuous efforts in drug delivery system development, structural optimization, safety assessment, and in-depth analysis of the mechanism of action. With the continuous deepening of research, thiocyanate is expected to become a lead compound for the development of new therapeutic drugs, contributing to the cause of human health.
The discovery of natural product drugs is a field full of opportunities and challenges, and the research process of thiocyanate once again proves the important value of natural products as a source of drugs. Through the organic combination of modern pharmacology, medicinal chemistry, and drug delivery technology, sulforaphane and its derivatives are expected to achieve clinical translation in the future, bringing new treatment options to patients.
