4-Methylumbelliferone Chemical Properties

Melting point:

188.5-190 °C(lit.)

Boiling point:

267.77°C (rough estimate)

Density 

1.1958 (rough estimate)

refractive index 

1.5036 (estimate)

storage temp. 

2-8°C

solubility 

Practically insoluble in water; slightly soluble in ethanol, ether,chloroform; soluble inmethanol

form 

Crystalline Powder

pka

7.79(at 25℃)

color 

off-white to yellow

PH Range

Green 1 uorescent (0.0) to weak blue 1 uorescent (2.0);Weak blue 1 uorescent (6.5) blue 1 uorescent (8.0)

Water Solubility 

slightly soluble

λmax

221nm, 251nm, 322nm

Merck 

14,4854

BRN 

142217

Stability:

Stable. Combustible. Incompatible with strong oxidizing agents.

Major Application

color filter, electroluminescent displays, document security processes, lasers, integrated circuits, liquid crystal displays, surface brightening composition, oil products, teeth whitening agent, lysosomal enzyme assay, substrate for lipase, determining protein-protein-interactions in living cells, Antitrypanosomal, antileishmanial, anticancer, antiHIV, antimalarial, antibacterial, antifungal

InChIKey

HSHNITRMYYLLCV-UHFFFAOYSA-N

LogP

2.370 (est)

CAS DataBase Reference

90-33-5(CAS DataBase Reference)

NIST Chemistry Reference

Coumarin, 7-hydroxy-4-methyl-(90-33-5)

EPA Substance Registry System

4-Methylumbelliferone (90-33-5)

Safety Information

Hazard Codes 

Xi,Xn

Risk Statements 

36/37/38-20/21/22

Safety Statements 

26-37/39-36

WGK Germany 

2

RTECS 

GN7000000

Hazard Note 

Irritant

TSCA 

Yes

HS Code 

29329990

Toxicity

LD50 oral in rat: 3850mg/kg

MSDS

• Language:English Provider:7-Hydroxy-4-methylcoumarin
• Language:English Provider:ACROS
• Language:English Provider:SigmaAldrich
• Language:English Provider:ALFA

4-Methylumbelliferone Usage And Synthesis

Chemical Properties

Off-white to yellow crystals. Soluble in ethanol, acetic acid, alkali solutions, and ammonia. Slightly soluble in hot water, ether, and chloroform. Exhibits blue fluorescence when exposed to concentrated sulfuric acid.

Originator

Odeston,Merck

Uses

4-methylumbelliferone (4-MU) is a dietary supplement that inhibits hyaluronic acid (HA) synthesis. HA is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. 4-MU is an already approved drug in Europe and Asia called “hymecromone” where it is used to treat biliary spasm.

Preparation

4-Methylumbelliferone is obtained by the cyclization reaction between resorcinol and ethyl acetate. Concentrated sulfuric acid is cooled to below 10 ° C, and a solution prepared from resorcinol and ethyl acetate is slowly added to the stirring solution. After dropping it completely, let it stand for 12 hours. Then, the reaction mixture is added into ice-cold water. The precipitate is filtered out and purified with a dilute sodium hydroxide solution and dilute sulfuric acid to obtain the final product.

Definition

ChEBI: 4-methylumbelliferone is a hydroxycoumarin that is umbelliferone substituted by a methyl group at position 4. It has a role as an antineoplastic agent and a hyaluronic acid synthesis inhibitor. It is functionally related to an umbelliferone.

Manufacturing Process

Resorcin reacted with 3-oxo-butyric acid ethyl ester in the presence sulfuric acid and phosphorous pentaoxide and 4-methyl-7-hydroxycoumarine (hymecromone) was obtained.

Therapeutic Function

Choleretic, Spasmolytic, Sunscreen agent

General Description

4-Methylumbelliferone is a useful indicator for nitric acid determination and enzyme activity investigation. It emits fluorescence in alkaline solution and Standard for the fluorometric determination of enzyme activity. Highly fluorescent in alkaline solution. Fluorescence: max Abs. l = 360nm, max. Em. l = 449nm; pH > 9.

Air & Water Reactions

Insoluble in water.

Fire Hazard

Flash point data for 4-Methylumbelliferone are not available. 4-Methylumbelliferone is probably combustible.

Pharmaceutical Applications

4-Methylumbelliferone is primarily used in synthesizing medicinal compounds and as a building block for fluorescent probes. Applications include synthesis of:
coumarin triazole derivatives as potential antimicrobial agents.
coumarin salen-based fluorescence sensors for Mg2+ detection.
pyranocoumarin derivatives as anti-hyperglycemic and anti-dyslipidemic agents.
coumarin piperazine derivatives as potential multireceptor atypical antipsychotics.
4-methylumbelliferyl T-antigen as a substrate for endo-α-N-acetylgalactosaminidase.

Biological Activity

4-methylumbelliferone is a hyaluronic acid (ha) synthesis inhibitor. 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.

Safety Profile

Moderately toxic by ingestion and intraperitoneal routes. An experimental teratogen. Experimental reproductive effects. When heated to decomposition it emits acrid smoke and irritating fumes.

in vitro

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. the mechanism still needs to be clarified, although several studies revealed that the anticancer effects of mu are mediated by inhibition of ha signal pathway. in a previous study the regulation of ha synthesis was demonstrated by ceramide, and now show how mu activated nsmase2 generates ceramides and mediates mu modulated inhibition of ha synthesis (cell migration and invasion, and apoptosis of tumor cells). using a ha enriched mouse oligodendroglioma cell line g26-24, it was found that mu elevated the activity of nsmase2 and enhanced ceramide levels, which in turn potentiated phosphatase pp2a activity. further, the activated pp2a decreased phosphorylation of akt, reduced activities of ha synthase2 (has2) and calpains, and blocked both the synthesis of ha, and the migration and invasion of g26-24 tumor cells. in addition, mu mediated ceramide induced activation of p53 and caspase-3, decreased sirt1 expression and deduced g26-24 viability. the mechanism of the mu anticancer therefore initially involves nsmase2/ceramide/pp2a/akt/has2/caspase-3/p53/sirt1 and the calpain signaling pathway, indicating that ceramides play a important role in the ability of a tumor to become aggressively metastatic and grow [1].

target

P450 (e.g. CYP17) | NADPH-oxidase | PKC | ROS

IC 50

0.4 mm

Purification Methods

Purify it by recrystallisation from EtOH. It is very slightly soluble in cold H2O (solubility at 37o is 0.22%), slightly soluble in Et2O and CHCl3, but soluble in MeOH and AcOH. It has a blue fluorescence in aqueous EtOH and has UV: 221, max 251 and 322.5nm (MeOH). The IR has 3077 br, 1667, 1592, 1385, 1267, 1156, 1130 and 1066 cm-1.max The acetate has m 153-154o. [Woods & Sapp J Org Chem 27 3703 1962, Beilstein 18 III/IV 332, 18/1 V 439.]

References

[1] qin j, kilkus j, dawson g. the hyaluronic acid inhibitor 4-methylumbelliferone is an nsmase2 activator-role of ceramide in mu anti-tumor activity. biochim biophys acta. 2016 feb;1861(2):78-90.
[2] Mustafa, Yasser Fakri et al. “4-Methylumbelliferone And Its Derived Compounds: A Brief Review Of Their Cytotoxicity.” The Egyptian Journal of Chemistry (2021): 0-0.
[3] Essa, Marwa Labib et al. “Dual targeting nanoparticles based on hyaluronic and folic acids as a promising delivery system of the encapsulated 4-Methylumbelliferone (4-MU) against invasiveness of lung cancer in vivo and in vitro.” International journal of biological macromolecules (2022): n. pag.

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