Synonym name:
Catalogue No.: BP1318
Cas No.: 24276-84-4
Formula: C₁₀H₉NaO₄
Mol Weight: 216.168
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.

HPLC of Sodium Ferulate

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

Introduction/Overview

Cardiovascular disease is one of the leading causes of death and disability worldwide, with thrombosis being a common pathological basis for major cardiovascular and cerebrovascular events such as myocardial infarction and ischemic stroke. Antiplatelet therapy is the cornerstone of preventing and treating arterial thrombotic diseases. However, traditional antiplatelet drugs represented by aspirin and clopidogrel have problems such as gastrointestinal injury, increased risk of bleeding, and resistance in some patients. Therefore, searching for efficient and low toxicity new antiplatelet drugs from natural products has always been an important direction in drug development. Sodium ferulate, as the sodium salt form of ferulic acid, the main active ingredient in traditional Chinese medicines such as Chuanxiong and Danggui for promoting blood circulation and removing blood stasis, has become a highly regarded natural source candidate drug due to its good water solubility and stability. This article aims to systematically review the chemical properties and pharmacological activities of sodium ferulate, especially its molecular mechanism of antiplatelet aggregation, drug evaluation, and clinical application prospects, in order to provide comprehensive academic references for the in-depth research and development of this compound.

Chemical structure and physicochemical properties

Sodium Ferulate, also known as 4-hydroxy-3-methoxycinnamate sodium, has a CAS number of 24276-84-4. Its molecular formula is C10H9NaO4 and its molecular weight is 194.1860. Structurally, sodium ferulate is an organic sodium salt formed by replacing the proton on the 3-hydroxy (phenolic hydroxyl) group of Ferulic acid with a sodium ion. Its parent nucleus structure is a derivative of cinnamic acid (cinnamic acid), containing a benzene ring (ring A) with two substituents, methoxy (- OCH3) and hydroxyl (- OH), and an acrylic side chain. This structure gives it the characteristics of both phenolic compounds and cinnamic acid derivatives.

The key physicochemical property parameters are as follows: the calculated lipid water partition coefficient (LogP) is about 1.84, indicating that the compound has a certain degree of lipophilicity, but overall tends to be hydrophilic. The topological polar surface area (TPSA) is 66.76 Å ², reflecting the proportion of polar groups (sodium carboxylate, phenolic hydroxyl, methoxy) in the molecule. Its water solubility is significantly better than its parent ferulic acid, reaching about 1.65 mg/mL, mainly due to the increased ionization degree of carboxylic acid groups after salt formation, greatly improving its formulation and in vivo absorption characteristics. Preliminary evaluation of its drug properties shows that its blood-brain barrier permeability is low, suggesting that its pivotal role may be limited; HERG inhibition is negative, indicating a lower risk of causing QT interval prolongation in the heart; The Ames test result is 0.0, indicating that it has no significant genetic toxicity. These physicochemical and pharmacological parameters together outline a molecular profile with great potential for development.

Plant sources and extraction methods

Ferulic acid is widely present in the plant kingdom and is a constituent unit of important biomolecules such as lignin and ferulic acid polysaccharides in the cell wall. It often exists in free or esterified form. In traditional Chinese medicine, herbs rich in ferulic acid often have the effects of promoting blood circulation, removing blood stasis, and relieving pain. Its main plant sources include:
1. Umbelliferae plants The rhizomes of Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels are the traditional and main sources of ferulic acid. The ferulic acid in Chuanxiong often synergizes with components such as ligustrazine to exert cardiovascular protective effects.
2. Poaceae plants Grain by-products such as rice bran, wheat bran, and corn bran, among which ferulic acid is often combined with hemicellulose such as arabinoxylan through ester bonds, are abundant and important raw materials for industrial extraction.
3. Other plants Ferula assa foetida L. resin, coffee beans, and various fruits and vegetables are also distributed.

The preparation of sodium ferulate usually involves two steps: first, extracting ferulic acid from plant materials, and then conducting a salt formation reaction.
1. Ferulic acid extraction：
* Alkali extraction and acid precipitation method The most classic method. By utilizing the characteristic of salt formation and dissolution of ferulic acid under alkaline conditions, the raw materials are leached with alkaline solutions such as sodium hydroxide, and then acidified to release ferulic acid. This method is simple, but it may cause partial degradation of ferulic acid due to strong alkaline and acidic conditions.
* Enzymatic hydrolysis Targeting esterified ferulic acid in grains, cellulase and xylanase are used to cleave the ester bond between ferulic acid and polysaccharides, resulting in mild release of ferulic acid under mild conditions and high product purity. This is the development direction of green extraction.
* Ultrasonic/Microwave Assisted Extraction Utilizing physical fields to enhance mass transfer, significantly shorten extraction time, and improve extraction efficiency.
* Supercritical CO2 extraction Suitable for fat soluble components, it has a certain effect on free ferulic acid, but often requires the addition of entrainers, resulting in higher costs.
2. Salting process Dissolve the purified ferulic acid in an appropriate amount of ethanol or water, add a calculated amount of sodium hydroxide or sodium carbonate solution dropwise while stirring, control the pH, and after complete reaction, concentrate, crystallize, and dry to obtain sodium ferulic acid. Modern technology emphasizes the control of crystallization conditions to obtain high-purity and suitable crystalline products.

Pharmacological activity research

Sodium ferulate has a wide range of pharmacological activities, with its core functions revolving around antioxidant and anti-inflammatory effects, and extending to multi system protective effects.

1. Antiplatelet aggregation effect This is the most widely studied and extensively researched core pharmacological activity of sodium ferulate. Numerous in vitro and in vivo experiments have confirmed that sodium ferulate can significantly inhibit platelet aggregation induced by various inducers such as adenosine diphosphate (ADP), arachidonic acid (AA), collagen, and thromboxane A2 analog (U46619). Its strength of action may be weaker than some potent chemical drugs, but it has the characteristics of multi-target and mild action. While preventing thrombosis, it may be accompanied by a lower risk of bleeding, which has important clinical significance.

2. Antioxidant and free radical scavenging activity The phenolic hydroxyl group in sodium ferulate molecules is a natural antioxidant group that can effectively remove reactive oxygen species/nitrogen species such as superoxide anions (O2 · -), hydroxyl radicals (· OH), and peroxynitrite (ONOO -), inhibit lipid peroxidation, and protect biological membranes, proteins, and DNA from oxidative damage. This function is the basis for its protective effects in multiple systems such as cardiovascular, cerebrovascular, neurological, and hepatic systems.

3. anti-inflammatory effect Sodium ferulate can inhibit the production of nitric oxide (NO), prostaglandin E2 (PGE2), as well as pro-inflammatory cytokines such as tumor necrosis factor - α (TNF - α), interleukin-1 β (IL-1 β), and IL-6 by macrophages stimulated by lipopolysaccharides (LPS). Its anti-inflammatory mechanism is closely related to the inhibition of the activation of inflammatory signaling pathways such as nuclear factor kappa B (NF - κ B) and mitogen activated protein kinase (MAPK).

4. Cardiovascular system protection：

   • cardioprotection In models of myocardial ischemia/reperfusion injury, doxorubicin induced cardiac toxicity, etc., sodium ferulate reduces myocardial cell damage and improves cardiac function through antioxidant, anti apoptotic, and anti-inflammatory effects.
   • Vascular protection Improve endothelial function, promote nitric oxide synthase (eNOS) activity, increase NO production, and dilate blood vessels; It can inhibit the abnormal proliferation and migration of vascular smooth muscle cells and prevent the formation of atherosclerotic plaque.

5. Protection of the nervous system Although its blood-brain barrier permeability is not high, studies have shown that it still exhibits neuroprotective effects in animal models such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease, which may be achieved through peripheral and partial central mechanisms such as reducing oxidative stress, inhibiting neuroinflammation, and cell apoptosis.

6. Other activities This also includes activities such as anti liver fibrosis, anti kidney injury, anti-tumor (inducing apoptosis, inhibiting metastasis), etc., most of which are associated with their core antioxidant and anti-inflammatory properties.

Mechanism of action and molecular targets

The anti platelet aggregation effect of sodium ferulate is the key to its use as a candidate drug for the treatment of cardiovascular and cerebrovascular diseases. Its mechanism involves intervention in multiple pathways of platelet activation, with diverse targets of action

1. Inhibition of arachidonic acid (AA) metabolic pathway：

   • Targeted cyclooxygenase (COX)Sodium ferulate can non selectively or mildly selectively inhibit the activity of COX-1 and COX-2 (i.e. PTGS1 and PTGS2). COX-1 is a key enzyme in platelets that converts AA into thromboxane A2 (TXA2), which is a powerful inducer of platelet aggregation and vasoconstrictor. By inhibiting COX-1, sodium ferulate reduces the production of TXA2, thereby inhibiting platelet aggregation. Meanwhile, its inhibition of COX-2 also contributes to its anti-inflammatory effect.
   • Antagonistic thromboxane A2 receptor (TBXA2R)Research suggests that sodium ferulate may act as a partial antagonist of the TXA2 receptor, blocking the binding of TXA2 to the receptor and thereby inhibiting TXA2 mediated platelet activation and vasoconstriction signaling.

2. Interference with platelet membrane receptor signals：

   • Antagonistic ADP receptor (P2Y12)The P2Y12 receptor (gene name P2RY12) is the core receptor for ADP induced platelet aggregation and amplification, and is also the target of clopidogrel. Sodium ferulate has been shown to inhibit the binding of ADP to P2Y12 receptors or interfere with their downstream signals, thereby blocking platelet activation through the ADP pathway.
   • Affects integrin α IIb β 3 (GPIIb/IIIa)The final aggregation of platelets depends on the activation of integrin α IIb β 3 (encoded by the ITGA2B and ITGB3 genes), which allows it to bind to ligands such as fibrinogen and bridge adjacent platelets. Sodium ferulate may indirectly reduce the activation and exposure of α IIb β 3 through upstream signal inhibition. There are also studies suggesting that it may directly interfere with the function of the integrin.
   • Acting on other receptors It may also have a certain modulation effect on upstream activation signals such as collagen receptor GPVI and thrombin receptor PAR-1.

3. Affects intracellular signal transduction and second messenger：

   • Regulating cyclic nucleotide levels Sodium ferulate may reduce the degradation of cyclic adenosine monophosphate (cAMP) by inhibiting the activity of phosphodiesterases such as PDE3A. Elevated levels of cAMP in platelets are a classic pathway for inhibiting platelet activation.
   • Inhibit calcium ion mobilization Platelet activation is accompanied by a sharp increase in intracellular calcium ion concentration ([Ca2+] i). Sodium ferulate can inhibit the release of calcium ions from the endoplasmic reticulum and extracellular calcium influx through various pathways, stabilizing the calcium homeostasis in platelets.

4. Upstream regulation based on antioxidant and anti-inflammatory properties Oxidative stress and inflammation are important promoting factors for platelet overactivation and thrombus formation. The strong antioxidant capacity of sodium ferulate can clear reactive oxygen species that activate platelets, protect endothelial cells, and reduce the production of platelet adhesion promoting factors such as von Willebrand factor (vWF) release. Its anti-inflammatory effect is achieved by inhibiting pathways such as NF - κ B, downregulating the expression of pro thrombotic mediators such as tissue factor (TF) and P-selectin, and creating an anti thrombotic environment at the vascular wall level.

In summary, sodium ferulate exerts its antiplatelet effect through a synergistic mode of "multi-target, multi pathway" action, which is different from most single target chemical drugs. This may be the molecular basis for its relatively mild and well-balanced action.

Evaluation of drug properties and pharmacokinetics

Based on its physical and chemical properties, sodium ferulate exhibits good medicinal potential. Its good water solubility is beneficial for making injections or oral solid preparations. The LogP value is moderate, indicating that it has a certain degree of membrane permeability. No hERG inhibition and genotoxicity warning, with a high safety threshold.

Pharmacokinetic studies (mainly based on animal experiments and some human studies) revealed the characteristics of its in vivo processes:
* absorb After oral administration, it is absorbed in the upper part of the small intestine at a faster rate. Its sodium salt form increases solubility and may improve absorption. But the first pass effect may be more pronounced.
* distribution After absorption, it quickly distributes to various tissues throughout the body, with higher concentrations in organs with abundant blood flow such as the liver, kidneys, and lungs. Due to its high polarity and low blood-brain barrier permeability, its distribution in the central nervous system is limited, which is consistent with the predicted physical and chemical properties.
* Metabolism Sodium ferulate undergoes extensive metabolism in the body. The main metabolic pathways include: 1)Combination reaction Combining with glucuronic acid or sulfuric acid to generate corresponding complexes is its main elimination method; 2） Degradation reaction The hydrogenation reduction of side chain double bonds and demethylation of benzene rings produce various metabolites, such as dihydroferulic acid and vanillic acid. Some of these metabolites still have biological activity.
* excretion Mainly excreted in the form of metabolites through the kidneys from urine, the excretion amount can reach the vast majority of the administered dose within 24 hours. A small amount is excreted from feces through bile.
* Pharmacokinetic characteristics It usually exhibits characteristics of a two compartment model, with a relatively short elimination half-life, suggesting that multiple daily doses may be necessary to maintain effective blood drug concentrations. Its pharmacokinetic behavior may be influenced by factors such as liver function and concomitant medication (affecting metabolic enzymes).

At present, sodium ferulate has been approved for clinical use as a chemical drug (raw material and formulation) in China, mainly for the adjuvant treatment of ischemic cardiovascular and cerebrovascular diseases, which provides a clinical data basis for further pharmacokinetic and drug interaction research.

Clinical application prospects and prospects

Sodium ferulate is currently used in clinical practice as an adjuvant therapy for thrombotic diseases such as coronary heart disease and cerebral infarction, often in combination with drugs such as aspirin. The clinical application prospects and future research directions mainly focus on the following aspects:

1. As a supplement or alternative to antiplatelet therapy For patients who cannot tolerate aspirin gastrointestinal reactions, have resistance to clopidogrel, or are at high risk of bleeding, sodium ferulate may provide a relatively mild option. Its multi-target mechanism of action may also bring more comprehensive antithrombotic benefits.
2. Potential in the field of thrombosis inflammation co treatment Many thrombotic diseases (such as atherosclerosis) are accompanied by significant inflammatory processes. Sodium ferulate has dual characteristics of antiplatelet and anti-inflammatory, which may give it unique advantages in the treatment of such diseases, achieving a synergistic effect of "anti thrombotic" and "anti-inflammatory".
3. Combination therapy strategy Study the combination of sodium ferulate and existing antiplatelet drugs (such as low-dose aspirin and P2Y12 inhibitors) to explore whether it can enhance antithrombotic efficacy or overcome drug resistance without significantly increasing bleeding risk.
4. Formulation innovation and optimization To address the issue of its short half-life, develop sustained-release and controlled release formulations (such as sustained-release tablets, microspheres, transdermal patches, etc.) to prolong the duration of action and improve patient compliance. The use of nanotechnology (such as liposomes and polymer nanoparticles) for encapsulation may improve its targeting (such as targeting diseased vascular endothelium or activated platelets), and may to some extent increase its blood-brain barrier permeability, expanding its application in neuroprotection.
5. Structural Modification and New Drug Development Using ferulic acid as the parent nucleus, structural modification is carried out to enhance its activity intensity, target selectivity, metabolic stability, and oral bioavailability, and to develop novel derivatives with independent intellectual property rights.
6. In depth study on the mechanism of action and biomarkers Using proteomics, metabolomics and other technologies to more accurately elucidate its multi-target network; Search for biomarkers that can predict its efficacy or adverse reactions, and achieve personalized medication.

The challenge also exists: as a derivative of natural products, its strength of action is usually weaker than that of synthetic drugs; The multi-target characteristic is both an advantage and makes the precise analysis and quality control of its mechanism of action complex; More large-scale, randomized controlled clinical studies are needed to confirm its long-term efficacy and safety, especially in comparison to standard therapies.

Conclusion

Sodium ferulate, a natural derivative derived from traditional Chinese medicine for promoting blood circulation and removing blood stasis, has become a distinctive molecule in the development of modern cardiovascular and cerebrovascular drugs due to its clear chemical structure, good physical and chemical properties, and multiple pharmacological activities centered on antiplatelet aggregation. It acts on multiple targets such as COX, P2Y12, TXA2 receptor, integrin α IIb β 3, and synergizes its strong antioxidant and anti-inflammatory abilities to construct a multi pathway synergistic anti thrombotic network. Although further exploration is needed in terms of the strength of action and depth of mechanism, its "multi-target, relatively mild" characteristics provide new solutions for the bleeding risk and drug resistance issues faced by current antiplatelet therapy. In the future, through in-depth mechanism research, dosage form innovation, clinical validation, and rational drug design based on structure, sodium ferulate and its derivatives are expected to play a more important clinical value in the prevention and treatment of thrombotic diseases, especially in complex pathological states that require both antithrombotic and anti-inflammatory effects. They will become one of the bridges connecting the wisdom of traditional Chinese medicine with modern precision medicine.