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| 25mg |
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Acacetin is a novel and potent Flavonoid that is derived from Dendranthema morifolium. Acacetin causes cell cycle arrest, apoptosis, and autophagy in cancer cells by docking in the ATP-binding pocket of PI3Kγ . Acacetin can be used for research on diseases associated with pain because it has potential anti-inflammatory and anti-cancer activity.
| Targets |
Acacetin functions as a multi-target agent, modulating numerous signaling pathways and directly binding to multiple molecular targets. Based on network pharmacology and molecular docking analyses, combined with experimental validation, the central experimentally supported targets of acacetin include epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and the serine/threonine kinase AKT (also known as protein kinase B, PKB). Acacetin directly binds to STAT3, as confirmed by pull-down assays, drug affinity responsive target stability (DARTS), and cellular thermal shift assays (CETSA), thereby inhibiting STAT3 phosphorylation at the tyrosine 705 residue and nuclear translocation. In cardiovascular systems, acacetin uniquely inhibits multiple atrial-specific potassium channel currents, including IKur (ultra-rapid delayed rectifier potassium current), IK.ACh (acetylcholine-activated potassium current), ISK (calcium-activated small conductance potassium current), and Ito (transient outward potassium current), contributing to its anti-atrial fibrillation effects. Acacetin also activates the Nrf2/HO-1/SOD antioxidant pathway, regulates PI3K/Akt/mTOR, Sirt1/AMPK/PGC-1α, TGF-β1/Smad3, and NF-κB signaling pathways, and inhibits monoamine oxidase A and B (MAO-A and MAO-B).
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| ln Vitro |
Acacetin (5,7-Dihydroxy-4'-methoxyflavone; 10-200 μM; 24 hours) decreases cell viabilities in a dose-dependent manner.
Human normal glial cell line HEB and non-tumorigenic epithelial cell line MCF-10A are not significantly affected by acetin[1]. Acacetin (50-150 μM; 24 hours) induces apoptosis and autophagy and causes G2/M cell cycle arrest[1]. Acacetin (50-150 μM; 24 hours) causes dose-dependent reductions in the levels of PI3Kγ-p110, p-AKT, p-mTOR, p-p70S6K and p-ULK. Acacetin demonstrates potent in vitro anticancer activity across multiple cancer cell lines with varying IC50 values. In human pharyngeal carcinoma FaDu cells, acacetin induced dose-dependent cell death with an IC50 of approximately 41.9 μM, triggering both death receptor-mediated extrinsic and mitochondria-mediated intrinsic apoptotic pathways. In prostate cancer DU145 cells, acacetin suppressed cell viability by inducing apoptosis, targeting the Akt and NF-κB signaling pathways via inhibition of IκBα and NF-κB phosphorylation in a dose-dependent manner. In cardiovascular research, acacetin (0.3–3 μM) significantly decreased apoptosis and reactive oxygen species (ROS) production in both primary cultured neonatal rat cardiomyocytes and H9C2 cells under hypoxia/reoxygenation (H/R) injury conditions; it reduced pro-apoptotic proteins Bax and cleaved caspase-3, increased anti-apoptotic Bcl-2 expression, suppressed pro-inflammatory cytokines (TLR4, IL-6), increased anti-inflammatory cytokine IL-10, and elevated antioxidants Nrf2 and HO-1 in a concentration-dependent manner. In lung epithelial A549 cells, acacetin increased cell viability, reduced TNF-α, IL-6, IL-17 and IL-1β levels, and increased NAD+ levels and NAD+/NADH ratio under TNF-α-stimulated inflammatory conditions. Additionally, acacetin inhibits aldose reductase (ALR2) by forming a hydrogen bond with Tyr48, and inhibits sortase A (SrtA) by binding to residues Arg-139 and Lys-140. |
| ln Vivo |
Acacetin (5,7-Dihydroxy-4'-methoxyflavone; 5, 20 mg/kg/day; orally; for 3 days) significantly suppresses microglial activation in an LPS-induced neuroinflammation mouse model[2].
Acacetin (25 mg/kg/day; orally; for 3 days) lowers neuronal cell death in an animal model of ischemia[2]. Acacetin (1.8-56.2 mg/kg/day; intraperitoneal; single dose) reduces visceral and inflammatory nociception and prevents the formalin-induced oedema[3]. Acacetin demonstrates significant therapeutic efficacy in various animal disease models. In xenografted nude mice bearing STAT3-activated DU145 prostate cancer cells, acacetin treatment effectively inhibited tumor growth. In cardiovascular studies, acacetin provided extensive cardiovascular protection against ischemia/reperfusion injury, cardiomyopathies/heart failure, autoimmune myocarditis, pulmonary artery hypertension, vascular remodeling, and atherosclerosis in rodent models, primarily through restoring the Sirt1/AMPK/PGC-1α signaling pathway and activating Nrf2/HO-1/SOD antioxidant defenses. In a mouse model of LPS-induced acute lung injury, acacetin (20–50 mg/kg) reduced mortality (50 mg/kg achieving ~60% survival, 20 mg/kg ~46.7%), rescued lung histopathologic damage, suppressed myeloperoxidase activity, and reduced pro-inflammatory cytokines TNF-α, IL-6, IL-17 and IL-1β. In a rat cerebral ischemia-reperfusion (MCAO) model, acacetin (low and high doses) decreased neurological deficit scores and cerebral infarction volume, lowered IL-1β, IL-6, TNF-α and MDA levels, elevated SOD and GSH levels, and regulated TLR4/NLRP3 signaling pathway-related proteins. In apolipoprotein E-deficient (apoE−/−) mice, acacetin treatment attenuated atherosclerosis by increasing reductase levels and decreasing plasma inflammatory factor levels. In a gastric ulcer rat model, acacetin (25 mg/kg, intraperitoneal) ameliorated acetylsalicylic acid-induced gastric ulcers. |
| Enzyme Assay |
A typical protocol for evaluating acacetin’s binding to purified enzymes involves enzyme kinetic assays to determine inhibition constants. For MAO-A and MAO-B inhibition studies, acacetin is incubated with the respective human recombinant MAO enzymes (typically at 0.1–100 μM) in appropriate buffer (e.g., 0.1 M potassium phosphate buffer, pH 7.4) at 37°C for 20 minutes. The enzyme-inhibitor complex mixture is dialyzed overnight at 4°C against buffer to assess binding reversibility through equilibrium dialysis dissociation analysis. Residual enzyme activity is measured fluorometrically using specific substrates (e.g., kynuramine for MAO-A, benzylamine for MAO-B). Molecular docking simulations are performed to predict binding energies and binding modes at the enzyme active site; for MAO-B, the binding energy is reported as −44.2 kcal/mol, with Cys172 residue playing a critical role in hydrogen bonding with acacetin. For aldose reductase (ALR2) inhibition, the assay monitors fluorescence absorption of NADPH, and the inhibition rate is calculated to obtain IC50 values. For direct target engagement studies (e.g., STAT3 binding), a pull-down assay using biotinylated acacetin is performed, followed by Western blot detection, complemented by DARTS and CETSA methods for label-free validation.
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| Cell Assay |
A representative protocol for assessing acacetin’s anticancer activity in vitro uses MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assays. Cells (e.g., DU145 prostate cancer cells or A549 lung carcinoma cells) are seeded in 96-well plates at 5 × 10³ to 1 × 10⁴ cells per well and cultured overnight. Acacetin is dissolved in DMSO and then diluted in culture medium to final concentrations ranging from 0 to 100 μM (DMSO concentration ≤0.1%). Cells are treated with acacetin for 24–72 hours. MTT solution (0.5 mg/mL) is then added to each well and incubated for 4 hours at 37°C. The formazan crystals formed are dissolved in DMSO (150 μL per well), and absorbance is measured at 540–575 nm using a microplate reader. Cell viability is calculated as percentage relative to control wells, and IC50 values are determined by nonlinear regression analysis. For apoptosis analysis, flow cytometry using Annexin V-FITC/PI double staining is performed. For mechanistic studies, Western blotting is used to detect protein expression levels of signaling pathway markers (e.g., p-Akt, p-NF-κB, Bcl-2, Bax, cleaved caspase-3, SIRT1, Nrf2, HO-1). For ROS measurement, the fluorescent probe DCFH-DA is used, and fluorescence intensity is detected at excitation/emission wavelengths of 485/535 nm. For cytokine analysis, cell culture supernatants are collected and analyzed by ELISA kits for TNF-α, IL-6, IL-1β, and IL-10.
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| Animal Protocol |
Male C57BL/6 mice, 7 weeks of age[2]
5, 20 mg/kg Orally; once a day for 3 days A typical in vivo protocol for evaluating acacetin’s therapeutic effects involves rodent models. For anticancer studies, 4–6 week old female BALB/c nude mice are subcutaneously injected with cancer cells (e.g., 5 × 10⁶ DU145 cells in 0.1 mL PBS). When tumors reach approximately 100 mm³, mice are randomized into treatment groups (n = 6–10 per group) receiving intraperitoneal or oral acacetin (e.g., 10–50 mg/kg/day) or vehicle control, typically for 2–4 weeks. Tumor volumes are measured every 3–4 days using calipers; body weight is monitored; and at study termination, tumors are excised, weighed, and processed for histological and molecular analyses. For acute lung injury studies, male C57BL/6 mice (6–8 weeks old) are intraperitoneally injected with LPS (5–10 mg/kg) to induce ALI; acacetin (20–50 mg/kg) is administered intraperitoneally or orally 1 hour before or after LPS challenge; survival rates are observed for up to 72 hours; lung tissues are collected for histopathology (H&E staining), wet-to-dry ratio measurement, myeloperoxidase activity assay, and BALF analysis for inflammatory cytokines. For cerebral ischemia-reperfusion injury, the middle cerebral artery occlusion (MCAO) model is established in Wistar rats using the intraluminal suture method; neurological deficit scores and cerebral infarction volume (by TTC staining) are evaluated; brain tissues are collected for ELISA (IL-1β, IL-6, TNF-α, MDA, SOD, GSH) and Western blot (TLR4, NLRP3, NF-κB, Bcl-2, Bax). For cardiovascular studies, myocardial ischemia/reperfusion injury is induced by temporary ligation of the left anterior descending coronary artery. |
| ADME/Pharmacokinetics |
Acacetin exhibits poor oral bioavailability, primarily due to its poor solubility and low gastrointestinal luminal stability. In rat studies, acacetin showed very low solubility (≤119 ng/mL) and relatively low stability (27.5–62.0% remaining after 24 hours) in pH 7 phosphate buffer and simulated gastrointestinal fluids. A major portion (97.1%) of the initially injected acacetin dose remained unabsorbed in the jejunal segments, resulting in an oral bioavailability of only 2.34%. The time to reach maximum plasma concentration (Tmax) after oral administration is approximately 5 minutes (range 2–15 minutes). Systemic metabolism of acacetin occurs ubiquitously in various tissues, particularly most extensively in the liver, leading to very high total plasma clearance of 199 ± 36 mL/min/kg. Due to these pharmacokinetic limitations, prodrug strategies (e.g., highly water-soluble acacetin prodrugs) have been developed to enhance bioavailability and therapeutic efficacy. Acacetin also significantly alters the pharmacokinetics of co-administered drugs such as diazepam, indicating potential drug–drug interactions via modulation of cytochrome P450 enzymes.
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| References |
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| Additional Infomation |
5,7-Dihydroxy-4'-methoxyflavonoid is a monomethoxyflavonoid, a 4'-methyl ether derivative of apigenin. It possesses anticonvulsant properties and is also a plant metabolite. It is a dihydroxyflavonoid and a monomethoxyflavonoid, functionally related to apigenin. It is the conjugate acid of 5-hydroxy-2-(4-methoxyphenyl)-4-oxo-4H-chromene-7-ol. Acaciain has been reported in Caragana frutex, Crocus heuffelianus, and other organisms with relevant data.
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| Molecular Formula |
C16H12O5
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|---|---|
| Molecular Weight |
284.267
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| Exact Mass |
284.068
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| Elemental Analysis |
C, 67.60; H, 4.26; O, 28.14
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| CAS # |
480-44-4
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| Related CAS # |
480-44-4
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| PubChem CID |
5280442
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
518.6±50.0 °C at 760 mmHg
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| Melting Point |
260-265 °C(lit.)
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| Flash Point |
198.3±23.6 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.669
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| LogP |
3.15
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
21
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| Complexity |
424
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1C(=C([H])C(C2=C(C([H])=C(C([H])=C12)O[H])O[H])=O)C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])[H]
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| InChi Key |
DANYIYRPLHHOCZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H12O5/c1-20-11-4-2-9(3-5-11)14-8-13(19)16-12(18)6-10(17)7-15(16)21-14/h2-8,17-18H,1H3
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| Chemical Name |
5,7-dihydroxy-2-(4-methoxyphenyl)chromen-4-one
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| Synonyms |
NSC 76061; Acacetin
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~125 mg/mL (~439.7 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (7.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 5 mg/mL (17.59 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: 10 mg/mL (35.18 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 2.5 mg/mL (8.79 mM) in 0.5% CMC/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.5178 mL | 17.5889 mL | 35.1778 mL | |
| 5 mM | 0.7036 mL | 3.5178 mL | 7.0356 mL | |
| 10 mM | 0.3518 mL | 1.7589 mL | 3.5178 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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