90-33-5

Usage

Uses

Used in Pharmaceutical Industry:
4-Methylumbelliferone is used as a dietary supplement for inhibiting hyaluronic acid synthesis, which is a prominent component of the extracellular matrix in chronic inflammation sites, including type 1 diabetes, multiple sclerosis, and various malignancies.
Used in Europe and Asia:
4-Methylumbelliferone is used as a drug called "hymecromone" for treating biliary spasm.
Used in Analytical Chemistry:
4-Methylumbelliferone is used as an indicator in the determination of nitric acid and as a standard for the fluorometric determination of enzyme activity. Its fluorescence properties make it highly useful in kinetic investigations of enzyme activity.
Used in Research:
4-Methylumbelliferone is used as a fluorescent probe in alkaline solutions, with maximum absorption at 360 nm and maximum emission at 449 nm when the pH is greater than 9.
Used in Other Industries:
4-Methylumbelliferone is used as a choleretic, spasmolytic, sunscreen, and analytical reagent in various industries.

Originator

Odeston,Merck

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

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].

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.

InChI:InChI=1/C10H8O3/c1-6-4-10(12)13-9-5-7(11)2-3-8(6)9/h2-5,11H,1H3

Upstream product

• 26093-31-2 7-amino-4-methylcoumarin. 
• 3993-57-5 7-allyloxy-4-methyl-2H-chromen-2-one 
• 57582-92-0 acetoacetic acid-(3-hydroxy-phenyl ester) 
• 64-19-7 acetic acid 
• 603-69-0 ethyl 2-acetylacetoacetate 
• 108-46-3 recorcinol 
• 1007476-32-5 sodium ethyl acetylacetate enolate 
• 80265-04-9 4-methylumbelliferyl 2-acetamido-2-deoxy-α-D-glucopyranoside 
• 53643-14-4 4-methylcoumarin-7-yloxy tetra-N-acetyl-β-chitotetraoside 
• 18997-57-4 4-methylumbelliferyl β-D-glucopyranoside 
• 38597-12-5 4-methylumbellifenyl α-D-galactopyranoside 
• 53643-13-3 4-methylumbelliferyl β-D-N,N′,N′′-triacetylchitotrioside 
• 7446-70-0 aluminium trichloride 
• 2747-05-9 4-methylumbelliferyl acetate 

Downstream Products

• 17695-46-4 7-(propylcarbonyl)oxy-4-methyl-2H-1-benzopyran-2-one 
• 3993-57-5 7-allyloxy-4-methyl-2H-chromen-2-one 
• 112121-60-5 4-methyl-2-oxo-2H-chromen-7-yl 4-methylbenzoate 
• 304673-28-7 4-methyl-7-o-toluoyloxy-coumarin 
• 92020-19-4 7-(ethoxy-methyl-thiophosphinoyloxy)-4-methyl-coumarin 
• 2555-23-9 7-hydroxy-4-methyl-3-phenyl-chromen-2-one 
• 3361-13-5 4-methyl-2-oxo-2H-chromen-7-yl propionate 
• 2747-05-9 4-methylumbelliferyl acetate 
• 2555-29-5 8-acetyl-7-hydroxy-4-methyl-2H-chromen-2-one 
• 24416-78-2 7-(benzyloxy)-4-methyl-2H-chromen-2-one 
• 5826-85-7 7-dimethoxythiophosphoryloxy-4-methyl-coumarin 
• 20312-83-8 8-Benzoyl-7-hydroxy-4-methylcoumarin 
• 66185-72-6 7-(phenylcarbonyl)oxy-4-methyl-2H-1-benzopyran-2-one 
• 299-45-6 potasan 

Relevant academic research and scientific papers

Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells

The tunable nature of phosphoramidate linkers enables broad applicability as pH-triggered controlled-release platforms, particularly in the context of antibody-and small-molecule-drug conjugates (ADCs and SMDCs), where there remains a need for new linker technology. Herein, we explored in-depth the release of turn-on fluorogenic payloads from a homoserinyl-based phosphoramidate acid-cleavable linker. Kinetics of payload release from the scaffold was observed in buffers representing the pH conditions of systemic circulation, early and late endosomes, and lysosomes. It was found that payload release takes place in two key consecutive steps: (1) P-N bond hydrolysis and (2) spacer immolation. These two steps were found to follow pseudo-first-order kinetics and had opposite dependencies on pH. P-N bond hydrolysis increased with decreasing pH, while spacer immolation was most rapid at physiological pH. Despite the contrasting release kinetics of these two steps, maximal payload release was observed at the mildly acidic pH (5.0-5.5), while minimal payload release occurred at physiological pH. We integrated this phosphoramidate-payload linker system into a PSMA-targeted fluorescent turn-on probe to study the intracellular trafficking and release of a fluorescent payload in PSMA-expressing prostate cancer cells. Results showed excellent turn-on and accumulation of the coumarin payload in the late endosomal and lysosomal compartments of these cells. The release properties of this linker mark it as an attractive alternative in the modular design of ADCs and SMDCs, which demand selective intracellular payload release triggered by the pH changes that accompany intracellular trafficking.

A Mechanistic Study on the Non-enzymatic Hydrolysis of Kdn Glycosides

Sialic acids are biologically important carbohydrates that are prevalent throughout nature. We are interested in their intrinsic reactivity in aqueous solution and how such reactivity affects the design of substrates for investigation of enzymes that process these sugars. To probe the reactivity differences between two sialic acid family members N-acetylneuraminic acid and Kdn we measured the rate constants for hydrolysis of 4-nitrophenyl 3-deoxy-d-glycero-α-d-galacto-non-2-ulosonide in aqueous solution. The kinetic data is consistent with glycosidic C?O bond cleavage occurring via four mechanistic pathways, and these are: (i) hydronium ion-catalyzed hydrolysis of the neutral sugar; (ii) hydronium ion-catalyzed hydrolysis of the glycosidic carboxylate; (iii) water-catalyzed hydrolysis of the anionic glycoside; and (iv) base-promoted reaction of the anionic glycoside. To study the effects of C-5 substitution on the Kdn glycoside we made 4-nitrophenyl 5-O-methyl-α-Kdn glycoside and determined its rate constants for hydrolysis. All hydrolytic rate constants for both Kdn glycosides were larger than those reported for the parent N-acetyl-α-neuraminide. The water-catalyzed reaction (pathway iii) exhibited a βlg value of ?1.3±0.1. We conclude that the larger rate constants associated with C5-oxygen containing sialosides results from less steric congestion at the hydrolytic transition states than for the parent C-5 acetamido glycoside.

B(C6F5)3-catalyzed synthesis of coumarins via Pechmann condensation under solvent-free conditions

Tris(pentafluorophenyl)borane [B(C6F5)3] catalyzed simple, efficient and environmentally benign protocol has been developed for the Pechmann condensation using variety of phenols and β-ketoesters under solvent-free conditions to afford coumarin derivatives. The present protocol displayed significant advantages such as low catalyst loading, short reaction time, mild reaction conditions, low toxicity, easy work-up, high yields, and compatibility with other functional groups. In addition, it is a convenient, clean, and fast alternative approach for synthesizing variety of coumarin derivatives. Moreover, the applicability of this method towards large-scale synthesis demonstrated its suitability for the industrial application. Graphic abstract: [Figure not available: see fulltext.]

Nanostructured coumarin-based cobalt complex as an efficient, heterogeneous and recyclable catalyst for the three-component synthesis of benzo[b]pyran and 3,4-dihydropyrano[c]chromene derivatives

Abstract: An improved one-pot three-component reaction of carbonyl compounds (dimedon, 4-hydroxy coumarin and 1,3-cyclohexadion) with malononitrile and aryl aldehydes in aqueous media (H2O:EtOH) as a solvent with short reaction time for the synthesis of benzo[b]pyran and 3,4- dihydropyrano[c]chromane derivatives by using nanostructured coumarin-based cobalt complex as an efficient heterogeneous catalyst. The salient features of this new protocol include simple procedure, high yields, easy isolation of products without need to column chromatography and short reaction times. Also, the nanocatalyst was recovered by adding EtOH and reused five times without significant loss of its catalytic activity. Biological impact assessments of the complex were conducted by DNA cleavage ability assay and eukaryotic cell toxicity measurement. Although the complex showed single-strand DNA breakage under oxidative conditions, its high polar nature revealed a marked decrease in cell toxicity data due to the restriction on cell entry. Graphic abstract: [Figure not available: see fulltext.]

One-Pot Three-Component Synthesis of 2,4,5-Triaryl-1H-imidazoles Using Mn2+Complex of [7-Hydroxy-4-methyl-8-coumarinyl] Glycine as a Heterogeneous Catalyst

A highly efficient and simple synthesis of 2,4,5-trisubstituted imidazoles has been developed using highly reusable support‐free Mn2+complex of [7-hydroxy-4-methyl-8-coumarinyl] glycine as a heterogeneous catalyst via a one-pot three-component reaction of benzil, aldehydes and ammonium acetate as a nitrogen source. Moreover, this catalyst was characterized by various techniques such as field emission scanning electron microscope (FE-SEM), energy dispersive X-ray spectroscopy (EDX), FT-IR spectroscopy, powder X-ray diffraction (XRD), inductively coupled plasma (ICP) and thermal gravimetric analysis (TGA). Also, the catalyst is stable and could be reused for at least six times without significant loss of activity. Graphic Abstract: [Figure not available: see fulltext.]

Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads

Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids in Mtb. Therefore, Pks13 is a promising drug target for tuberculosis treatment. We used a structure-guided approach to identify novel chemotype inhibitors of Pks13 and assessed them using a Pks13 enzymatic assay and surface plasmon resonance. The structure–activity relationships (SAR) results demonstrated that the substituents at the 2, 5, and 6 positions of the 4H-chromen-4-one scaffold are critical for maintaining the MIC. Compound 6e with 2-hydroxyphenyl at the 2 position of the 4H-chromen-4-one scaffold, exhibited potent activity against Mtb H37Rv (MIC = 0.45 μg/mL) and displayed good Pks13 affinity and inhibition (IC50 = 14.3 μM). This study described here could provide an avenue to explore a novel inhibitor class for Pks13 and aid the further development of antituberculosis drugs.

A ratiometric fluorescent probe for the detection of β-galactosidase and its application

Herein, a coumarin fluorescent probe (Probe1) was developed for the ratiometric detection of β-galactosidase (β-gal) activity. The detection range was 0-0.1 U mL?1and 0.2-0.8 U mL?1, and the limit of detection (LOD) was 0.0054 U mL?1. Moreover, the luminous intensity of Probe1increased gradually with increase in β-gal activity. It could be observed under 254 nm UV irradiation by the naked eye. Furthermore, this method only required a small amount of sample (20 μL) and a short analytical time (30 min) for the detection of β-gal activity with a low LOD. Probe1was successfully used to detect β-gal activity in real fruit samples, and can be applied to the quantitative and qualitative detection of β-gal activity.

Peroxide-responsive boronate ester-coupled turn-on fluorogenic probes: Direct linkers supersede self-immolative linkers for sensing peroxides

Turn-on fluorogenic probes are commonly utilized for an efficient estimation of reactive oxygen species such as H2O2. In the present study, three different sets of turn-on fluorogenic probes for sensing H2O2 wer

Evaluation of borinic acids as new, fast hydrogen peroxide–responsive triggers

Hydrogen peroxide (H2O2) is responsible for numerous damages when overproduced, and its detection is crucial for a better understanding of H2O2-mediated signaling in physiological and pathological processes. For this purpose, various “off–on” small fluorescent probes relying on a boronate trigger have been prepared, and this design has also been involved in the development of H2O2-activated prodrugs or theranostic tools. However, this design suffers from slow kinetics, preventing activation by H2O2 with a short response time. Therefore, faster H2O2-reactive groups are awaited. To address this issue, we have successfully developed and characterized a prototypic borinic-based fluorescent probe containing a coumarin scaffold. We determined its in vitro kinetic constants toward H2O2-promoted oxidation. We measured 1.9 × 104 M-1·S-1 as a second-order rate constant, which is 10,000-fold faster than its well-established boronic counterpart (1.8 M-1·S-1). This improved reactivity was also effective in a cellular context, rendering borinic acids an advantageous trigger for H2O2-mediated release of effectors such as fluorescent moieties.

Alpha-L-fucosidase detection probe and preparation method and application thereof

The invention discloses an alpha-L-fucosidase detection probe. The structural general formula of the probe is shown in the specification, wherein in the formula I, R1 is an acetyl-protected monosaccharidyl or monosaccharidyl group; and R2 is a pyranonitrile group or a benzopyran nitrile group. The alpha-L-fucosidase detection probe prepared by the invention improves the detection sensitivity, can detect serum AFU with high selectivity, and can be used for kits or drugs for positioning and detecting cancer cells.