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Purity: ≥98%
4-Methylumbelliferone (Hymecromone; 4-MU) is a potent and selective inhibitor of hyaluronic acid (HA) biosynthesis with an IC50 of 0.4 mM. The activation of HAS2 and the over-production of HA are existed in many metastatic tumor cell lines. Increased synthesis of HA is often associated with increased metastatic potential and invasivity in tumor cells. 4-Methylumbelliferone (MU), an inhibitor of HA synthesis, has been studied as a potential anti-tumor drug on account of inhibiting the growth of primary tumors and distant metastasis of tumor cells.
| Targets |
4-Methylumbelliferone (Hymecromone; 4-MU) targets hyaluronan synthases (HAS1, HAS2, HAS3) to inhibit hyaluronan (HA) synthesis [1]
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| ln Vitro |
4-Methylumbelliferone (4-MU) has an impact on a number of crucial angiogenesis processes, such as adhesion, tube formation, proliferation of endothelial cells, and extracellular matrix remodeling. In the proliferation assay, the half-maximal inhibitory concentration (IC50) values for RF-24 endothelial cells and human microvascular endothelial cells were 0.37±0.03 mM and 0.65±0.04 mM, respectively. One-third of HMEC and five percent of RF-24 cells underwent apoptosis after receiving a 24-hour treatment with 2-methylumbellarone (2 mM). One hour of treatment with 1 mM 4-Methylumbelliferone resulted in a reduction of adherent endothelial cells of over 20%. In the tube formation assay, the minimal inhibitory doses for HMEC and RF-24 were 2 and 0.5 mM 4-Methylumbelliferone, respectively. Two endothelial cell lines were investigated, and after treatment with 4-Methylumbelliferone, the expression of matrix metalloproteinase 2 changed in various ways [1].
In human umbilical vein endothelial cells (HUVECs), 4-Methylumbelliferone (Hymecromone; 4-MU) (10–200 μM) dose-dependently inhibited cell proliferation. After 72 hours, the IC50 for proliferation inhibition was ~80 μM. It suppressed HUVEC migration (Transwell assay) by ~45% (50 μM), ~60% (100 μM), and ~75% (200 μM) compared to control [1] - 4-Methylumbelliferone (Hymecromone; 4-MU) (50–200 μM) inhibited HUVEC tube formation on Matrigel: at 100 μM, the number of tube branches decreased by ~70%, and tube length reduced by ~65%. It also reduced intracellular HA production by ~58% (100 μM) and ~72% (200 μM) in HUVECs [1] - At 100–200 μM, 4-Methylumbelliferone (Hymecromone; 4-MU) regulated angiogenesis-related factors in HUVECs: VEGF and bFGF mRNA levels decreased by ~55% and ~50% (200 μM), while thrombospondin-1 (TSP-1) mRNA level increased by ~2.3-fold (200 μM). Western blot showed downregulated VEGF protein (by ~60% at 200 μM) and upregulated TSP-1 protein (by ~2.1-fold at 200 μM) [1] |
| ln Vivo |
In the chick chorioallantoic membrane (CAM) angiogenesis model, 4-Methylumbelliferone (Hymecromone; 4-MU) (50, 100, 200 μg/egg) was topically applied on day 3 of incubation. At day 7, it dose-dependently inhibited blood vessel formation: 100 μg/egg reduced the number of blood vessels by ~55%, and 200 μg/egg by ~70%, compared to vehicle control [1]
- In the mouse corneal neovascularization model induced by bFGF pellet implantation, oral administration of 4-Methylumbelliferone (Hymecromone; 4-MU) (25, 50 mg/kg/day) for 7 days inhibited corneal neovascularization. The 50 mg/kg group showed a ~62% reduction in neovascularized area and a ~58% decrease in vessel density compared to control. Corneal HA content was reduced by ~55% (50 mg/kg) [1] |
| Enzyme Assay |
Hyaluronan synthase (HAS) activity assay: HUVECs were treated with 4-Methylumbelliferone (Hymecromone; 4-MU) (50–200 μM) for 24 hours. Cell lysates were prepared and incubated with UDP-glucuronic acid and UDP-N-acetylglucosamine (substrates for HA synthesis) in reaction buffer at 37°C for 2 hours. The synthesized HA was precipitated with cetylpyridinium chloride, and the amount of HA was quantified by a colorimetric assay using a HA detection kit. HAS activity was calculated based on HA production [1]
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| Cell Assay |
HUVEC proliferation assay: HUVECs were seeded in 96-well plates (3×103 cells/well) and treated with 4-Methylumbelliferone (Hymecromone; 4-MU) (10–200 μM) for 24–72 hours. MTT assay was performed to measure cell viability, and the IC50 value for proliferation inhibition was calculated [1]
- HUVEC migration and tube formation assay: For migration, HUVECs were seeded in the upper chamber of Transwell inserts, and 4-Methylumbelliferone (Hymecromone; 4-MU) (50–200 μM) was added to both upper and lower chambers. After 24 hours, migrated cells on the lower membrane were stained and counted. For tube formation, HUVECs (5×104 cells/well) were seeded on Matrigel-coated 24-well plates with 4-Methylumbelliferone (Hymecromone; 4-MU) (50–200 μM), and tube structures were photographed and analyzed for branch number and length after 6 hours [1] - Angiogenesis-related factor expression assay: HUVECs were treated with 4-Methylumbelliferone (Hymecromone; 4-MU) (100–200 μM) for 24 hours. Total RNA was extracted for RT-PCR to detect VEGF, bFGF, and TSP-1 mRNA levels. Cell lysates were prepared for Western blot to analyze VEGF and TSP-1 protein expression [1] |
| Animal Protocol |
Chick chorioallantoic membrane (CAM) model: Fertilized chicken eggs were incubated at 37°C with 60% humidity. On day 3, a window was opened on the eggshell, and 4-Methylumbelliferone (Hymecromone; 4-MU) (50, 100, 200 μg/egg) dissolved in PBS was topically applied to the CAM. Vehicle control eggs received PBS. On day 7, the CAM was photographed, and the number of blood vessels was counted using image analysis software [1]
- Mouse corneal neovascularization model: Female C57BL/6 mice (6–8 weeks old) were anesthetized, and a small incision was made in the cornea. A bFGF-soaked alginate pellet was implanted into the corneal stroma. 4-Methylumbelliferone (Hymecromone; 4-MU) was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered by oral gavage at 25 or 50 mg/kg/day for 7 days. Control mice received 0.5% CMC-Na. On day 7, mice were sacrificed, corneas were excised, stained with isolectin B4, and the neovascularized area and vessel density were analyzed by fluorescence microscopy [1] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
Known metabolites of 4-methylumbelliferone include 4-methylumbelliferone O-glucuronide. |
| Toxicity/Toxicokinetics |
In vitro toxicity: 4-methylumbelliferone (Hymecromone; 4-MU) (10–200 μM) showed no significant cytotoxicity to human umbilical vein endothelial cells (HUVECs) or normal human dermal fibroblasts, and cell viability remained above 85% at all tested concentrations [1]. In vivo toxicity: After oral administration of 4-methylumbelliferone (Hymecromone; 4-MU) (25–50 mg/kg/day for 7 consecutive days) to mice, no changes in body weight, food intake, or obvious toxic symptoms (such as somnolence or diarrhea) were observed. Serum ALT, AST, creatinine, and blood urea nitrogen levels were all within the normal range, and no abnormal lesions were found in liver and kidney histology [1].
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| References | |
| Additional Infomation |
β-Methylumbelliferone is a colorless crystal and insoluble in water. (NTP, 1992)
4-Methylumbelliferone is a hydroxycoumarin formed by replacing umbelliferone with a methyl group at the 4-position. It has antitumor activity and can inhibit the synthesis of hyaluronic acid. Its function is similar to that of umbelliferone. Umbelliferone has been reported to be found in Tripterygium wilfordii, Ferula foetida and other organisms with relevant data. 4-Methylumbelliferone is a metabolite of Saccharomyces cerevisiae and is present in or produced by Saccharomyces cerevisiae. A coumarin derivative with antispasmodic, choleretic and photoprotective effects. It is also used in analytical chemistry techniques to determine nitrate. 4-Methylumbelliferone (Hymecromone; 4-MU) is a natural coumarin derivative found in a variety of plants and is used clinically as a choleretic agent [1] - Its anti-angiogenic mechanism involves inhibiting the synthesis of hyaluronic acid (HA) by targeting hyaluronic acid synthase (HAS). Reduced hyaluronic acid (HA) accumulation impairs endothelial cell proliferation, migration, and tubular formation, and regulates the expression of angiogenesis-related factors (downregulating VEGF/bFGF and upregulating TSP-1) [1] - 4-methylumbelliferone (4-MU) has shown potential therapeutic value in angiogenesis-dependent diseases such as cancer, age-related macular degeneration, and inflammatory diseases [1] |
| Molecular Formula |
C10H8O3
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| Molecular Weight |
176.17
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| Exact Mass |
176.047
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| CAS # |
90-33-5
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| Related CAS # |
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| PubChem CID |
5280567
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| Appearance |
White to off-white solid powder
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| Density |
1.319 g/cm3
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| Boiling Point |
377.4ºC at 760 mmHg
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| Melting Point |
188.5-190 °C(lit.)
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| Flash Point |
174.5ºC
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| LogP |
1.807
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
13
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| Complexity |
257
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HSHNITRMYYLLCV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C10H8O3/c1-6-4-10(12)13-9-5-7(11)2-3-8(6)9/h2-5,11H,1H3
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| Chemical Name |
7-hydroxy-4-methylchromen-2-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (14.19 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (14.19 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (14.19 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50 mg/mL (283.82 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.6763 mL | 28.3817 mL | 56.7634 mL | |
| 5 mM | 1.1353 mL | 5.6763 mL | 11.3527 mL | |
| 10 mM | 0.5676 mL | 2.8382 mL | 5.6763 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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