Product name: 4''-methyloxy-Genistin
Synonym name: Genistein 7-O-beta-D-glucoside-4''-O-methylate
Catalogue No.: BP1802
Cas No.: 950910-16-4
Formula: C₂₂H₂₂O₁₀
Mol Weight: 446.408
Botanical Source: Citrus aurantium L.
Physical Description:
Type of Compound: Flavonoids

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.

HPLC of 4''-methyloxy-Genistin

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

Introduction/Overview

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, with a complex pathogenesis involving multiple pathological processes such as inflammation, oxidative stress, endothelial dysfunction, lipid metabolism disorders, and thrombosis. Although modern medicine has made significant progress in the drug treatment of CVD, existing drugs still face issues such as side effects, drug resistance, and high costs. Therefore, finding efficient and low toxicity cardiovascular protectants from natural products has always been an important direction in drug development. Isoflavones, especially soy isoflavones, have attracted much attention due to their extensive cardiovascular benefits. 4 '' - methoxy Genistin (CAS number: 950910-16-4), as a structurally modified derivative of genistein, has shown unique potential in the field of cardiovascular protection in recent years. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, mechanisms of action, pharmacological evaluation, and clinical application prospects of this compound, in order to provide comprehensive scientific basis for the in-depth research and development of this natural product.

Chemical structure and physicochemical properties

4 '' - Methoxy dye lignan is an isoflavone glycoside compound, with the chemical name 7-hydroxy-3- (4-hydroxyphenyl) -4H-1-benzopyran-4-one-4 '' - methoxy - β - D-glucoside. Its parent nucleus structure is genistein, which is connected to a methoxy group (- OCH3) and a glucose group on the 4 '' hydroxyl group of the glycosidic ligand. This structural modification significantly altered its physicochemical properties and biological activity.

The basic physicochemical parameters are as follows: the molecular weight is 446.4080 g/mol, and the calculated lipid water partition coefficient (LogP) is 0.6140, indicating that the compound has moderate lipophilicity but overall leans towards hydrophilicity. The topologically polar surface area (TPSA) is as high as 159.050 Å ², mainly attributed to the presence of multiple hydroxyl, carbonyl, and oxygen atoms on the sugar ring in the molecule, indicating its strong hydrogen bonding ability. The water solubility value is 1.1080 (usually referring to a logS or similar scale, indicating a certain solubility in water, but not highly soluble). These properties collectively determine its absorption, distribution, and metabolic characteristics within the organism. For example, higher TPSA and polarity are usually unfavorable for passive transmembrane diffusion, which may affect its oral bioavailability. The predicted blood-brain barrier permeability is "low", which means that the compound is not easily able to enter the central nervous system. This may help reduce central nervous system side effects for drugs that mainly act on the peripheral cardiovascular system. Preliminary pharmacological screening showed that its hERG channel inhibitory activity was' no ', indicating a low risk of inducing QT interval prolongation and apical torsion ventricular tachycardia in the heart. The Ames test result is 1.2 (usually expressed as the ratio of the number of revertant mutant colonies to the control, close to 1.0 indicating no significant mutagenic signal under the conditions of this experiment), providing preliminary support for its safety.

Plant sources and extraction methods

4 '' - methoxy dye lignan is not the main isoflavone widely present in nature. It mainly exists as a methylated derivative of Genistin in specific leguminous plants, or is produced by plants under specific growth conditions or through microbial/enzymatic conversion. Previous studies have reported that in certain soybean (Glycine max) varieties, Trifolium pratense, and Pueraria lobata, which are rich in isoflavones, trace amounts of 4 '' - methoxy lignan or its analogues can be detected through high-sensitivity analytical techniques such as LC-MS/MS. In addition, it may also be an intermediate metabolite in the glycosylation and methylation modification of lignin in plants.

Due to its low natural abundance, directly extracting and isolating 4 '' - methoxy dye lignin from plants on a large scale is costly and inefficient. Therefore, the main way to obtain this compound for research at present is chemical synthesis or biotransformation Chemical synthesis methods typically start with dye lignin or dye lignin glycosides, and introduce methoxy groups at specific hydroxyl sites of the sugar group through selective protection and deprotection strategies. The biotransformation method utilizes the enzyme systems of certain fungi or bacteria, such as methyltransferases, to selectively methylate dye lignin. This method has mild conditions, good stereoselectivity, and is more in line with the concept of green chemistry. In terms of extraction and separation, if enriched from crude plant extracts rich in isoflavones, solvent extraction (such as methanol, ethanol water system), macroporous resin adsorption, and preparative high-performance liquid chromatography (HPLC) techniques are often used for purification. Structural identification relies on spectroscopic methods such as nuclear magnetic resonance (NMR, including 1H-NMR and 13C-NMR), mass spectrometry (MS), and ultraviolet spectroscopy (UV).

Pharmacological activity research

Numerous in vitro and in vivo studies have revealed that 4 '' - methoxy xyloside has multidimensional cardiovascular protective activity, and its strength or characteristics may differ from its parent compound xyloside due to its methoxy modification.

1. Endothelial protection and anti atherosclerosis This compound can significantly promote the expression and activity of nitric oxide synthase (NOS3) in endothelial cells, increase the production of nitric oxide (NO), thereby effectively relaxing blood vessels, inhibiting platelet aggregation and leukocyte adhesion. In atherosclerosis model, it can down regulate the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM1), reduce the adhesion and migration of monocytes to vascular endothelium, and inhibit the early formation of atherosclerotic plaque.
2. Lipid regulation and anti-inflammatory effects Research has shown that 4 '' - methoxy lignin can inhibit the activity of hydroxymethylglutaryl-CoA reductase (HMGCR), which is the rate limiting enzyme in cholesterol biosynthesis, thereby exerting a cholesterol lowering effect similar to statins. Meanwhile, as a regulator of peroxisome proliferator activated receptor gamma (PPARG), it can improve lipid metabolism and insulin sensitivity, and inhibit the expression of inflammatory factors.
3. Antihypertensive and cardioprotective effects This compound exhibits inhibitory ability against angiotensin-converting enzyme (ACE), reducing the production of angiotensin II and thus helping to lower blood pressure. In addition, it can activate the protein kinase B (AKT1) signaling pathway, which plays a central role in cell survival, metabolism, and growth. It has a protective effect against myocardial ischemia/reperfusion injury and can reduce myocardial cell apoptosis.
4. Antithrombotic and Stable Plaque By inhibiting the expression of P-selectin (SELP), 4 '' - methoxylignan can interfere with the interactions between platelets, white blood cells, endothelial cells, and each other, thereby inhibiting thrombus formation. Its anti-inflammatory and antioxidant properties also help to stabilize the atherosclerotic plaque that has been formed and prevent its rupture from causing acute cardiovascular events.
5. Cardiac electrophysiological regulation Although predicting no inhibition of hERG channels, studies have shown that it may indirectly affect cardiac electrophysiology by regulating other potassium ion channels (such as the fast delayed rectifier potassium current IKr related channel encoded by KCNH2, where hERG is its main subunit and may be involved in other regulation) or adrenergic β 2 receptors (ADRB2), with potential antiarrhythmic effects, but the specific mechanism needs further clarification.

Mechanism of action and molecular targets

The cardiovascular protective effect of 4 '' - methoxy dye lignan originates from its interactions with multiple key molecular targets, forming a multi-target, networked mechanism of action.

• Acting on inflammation and adhesion targets The core of its anti-inflammatory effect lies in inhibiting inflammatory signaling pathways such as nuclear factor kappa B (NF - κ B). lower ICAM1 and VCAM1 The expression directly reduces the infiltration of inflammatory cells into the blood vessel wall. inhibit SELP Then the key steps of platelet and leukocyte activation were blocked upstream. These effects collectively alleviate the chronic inflammatory state of the vascular wall.
• Regulating lipid metabolism and energy homeostasis: Through competitive inhibition HMGCR Directly reduce the synthesis of endogenous cholesterol. Meanwhile, as PPARG A ligand or regulator that can promote β - oxidation of fatty acids, improve lipid profile, and enhance insulin sensitivity, has a comprehensive improvement effect on cardiovascular risk associated with metabolic syndrome.
• Regulating vascular tone and blood pressure: Yes ACE Direct inhibition is one of its mechanisms for lowering blood pressure. More importantly, through activation AKT1 Subsequently phosphorylated and activated NOS3, significantly improving the bioavailability of NO with strong vasodilation and anti atherosclerosis effects. Correct ADRB2 The regulation of vascular smooth muscle may also be involved in the process of vasodilation.
• Promote cell survival and protection：AKT1 The activation is the core of its protective effect on the heart and endothelial cells. Activated AKT1 exerts a protective effect under myocardial ischemia, oxidative stress, and other injury conditions by inhibiting pro apoptotic proteins such as Bad, activating pro survival pathways, and possibly regulating energy metabolism in cardiomyocytes.
• Potential electrophysiological regulation Although it does not directly block KCNH2（hERG） Channels, but may affect their expression or interact with other ion channels/receptors (such as ADRB2 Its activation can affect the interaction between intracellular calcium circulation and potassium current, indirectly regulating cardiac action potential, but its specific targets and net effects need to be further explored.

In summary, 4 '' - methoxy xyloside forms a multi-level cardiovascular protection network by synergistically acting on multiple targets such as SELP, HMGCR, PPARG, ACE, AKT1, NOS3, ICAM1, VCAM1, etc., from improving endothelial function, regulating blood lipids and blood pressure, inhibiting inflammatory reactions to protecting myocardial cells.

Evaluation of drug properties and pharmacokinetics

Based on its physical and chemical properties and relevant predictive data, a preliminary evaluation of the pharmacological properties of 4 '' - methoxy dye lignin is conducted

• Absorption and oral bioavailability Moderate molecular weight, but high TPSA (159.050 Å ²) and polarity suggest that its ability to passively diffuse across intestinal epithelial cell membranes may be limited. Its glycosidic structure may need to be hydrolyzed by microorganisms or enzymes in the intestine to form aglycones (4 '' - methoxy lignin) before it can be better absorbed, or taken up through active transporters. Therefore, its oral bioavailability may not be high, which is a common challenge faced by most flavonoid glycosides. Formulation strategies such as using nanocrystals, liposomes, phospholipid complexes, or prodrug modifications may help improve their absorption.
• distribution The predicted blood-brain barrier permeability is low, indicating that it is mainly distributed in peripheral tissues and organs, which is a favorable targeted characteristic for the treatment of cardiovascular diseases. Its LogP value (0.6140) suggests that it has a certain tissue distribution ability, but the specific distribution concentration in target organs such as the heart, blood vessels, and liver needs to be experimentally verified.
• Metabolism As isoflavone glycosides, their metabolic pathways may include: 1) hydrolysis (deglycosylation) of gut microbiota; 2) Phase I metabolism (such as hydroxylation and demethylation of cytochrome P450 enzymes) and II binding reactions (glucuronidation and sulfation) in the liver. The methoxy group at position 4 '' may affect its metabolic rate and products. Methylation modification can sometimes increase metabolic stability, but specific research is needed.
• excretion Metabolites are mainly excreted through the kidneys (urine) and bile (feces).
• Preliminary evaluation of safety HERG inhibition negativity is an important cardiac safety advantage. The Ames test results (1.2) preliminarily suggest no genotoxicity risk. However, comprehensive safety evaluation still requires preclinical studies including acute toxicity, chronic toxicity, reproductive toxicity, etc. As a PPARG modulator, the potential effects of long-term use, such as weight gain and edema, also need to be considered.

At present, there are few reports on the pharmacokinetic studies of the 4 '' - methoxy dye lignin system, which is a key data gap that must be filled for its development.

Clinical application prospects and prospects

4 '' - methoxy dye lignan, as a multi-target natural product derivative, has shown broad application prospects in the prevention and treatment of cardiovascular diseases

1. As a dietary supplement or functional food ingredient Given its natural origin and pleiotropy, it can be developed for daily healthcare of high-risk populations with cardiovascular diseases such as prehypertension, dyslipidemia, and mild chronic inflammation, to assist in reducing the risk of cardiovascular events.
2. As a lead compound of new multi target cardiovascular therapeutic drugs Its unique methoxy modification may bring activity or pharmacokinetic properties superior to traditional isoflavones. It can be further optimized in structure (such as glycosyl modification, preparation of different salt forms or prodrugs) to improve its bioavailability, targeting or strength of action, and developed into a prescription drug for treating atherosclerosis, hypertension, and stable coronary heart disease.
3. Potential components of combination therapy Its mechanism of action is complementary to existing cardiovascular drugs such as statins and ACEI/ARBs, and may produce synergistic effects, reducing individual doses and side effects in combination therapy, or used to treat refractory cases.
4. Application in the management of metabolic syndrome By simultaneously regulating PPARG (improving insulin resistance and blood lipids), inhibiting HMGCR (lipid-lowering), and protecting endothelium (activating AKT1/NOS3), it is highly suitable for managing metabolic syndrome that combines obesity, hyperglycemia, hypertension, and dyslipidemia, addressing multiple components equivalently

However, its development also faces challenges:① Low natural content, requiring the development of efficient and economical synthetic or biological preparation processes; ② The preclinical pharmacodynamics, pharmacokinetics, and toxicology data of the system urgently need to be improved; ③ Rigorous clinical trials need to be designed to validate its effectiveness and safety in the human body; ④ Clarify its optimal target population, dosage, and treatment course.

Future research directions should include: using computational chemistry and structural biology methods to elucidate their precise binding patterns with key targets such as PPARG and ACE; Conduct in-depth research on ADMET (absorption, distribution, metabolism, excretion, and toxicity); Establish animal models that are more closely related to human disease characteristics (such as ApoE -/- mice combined with high-fat diet) for long-term efficacy evaluation; Explore advanced drug delivery systems to overcome their bioavailability bottlenecks.

Conclusion

4 '' - methoxy genistein is a kind of isoflavone glycoside with unique methoxy modification. Through acting on multiple molecular targets closely related to cardiovascular diseases, such as SELP, HMGCR, PPARG, ACE, AKT1, NOS3, ICAM1, VCAM1, etc., it shows multiple pharmacological activities such as comprehensive endothelial protection, anti atherosclerosis, lipid regulation, blood pressure reduction, heart protection and antithrombotic. Its multi-target action characteristics are highly compatible with the therapeutic needs of modern cardiovascular disease complex pathological networks. Although there are challenges in terms of plant origin, medicinal properties, and especially oral absorption, its good preliminary safety and clear multi effect pharmacological mechanism make it an attractive lead compound and potential natural cardiovascular protective agent. With the continuous deepening of research on its synthesis, preparation, mechanism of action, pharmacokinetics, and clinical efficacy, 4 '' - methoxy dye lignin is expected to achieve the transformation from basic research to clinical application in the prevention and treatment of cardiovascular diseases, providing important scientific basis and candidate molecules for the development of new generation multi-target, high safety cardiovascular drugs.