1143-70-0

Basic information

• Product Name: 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
• Synonyms: 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one;3,8-DIHYDROXYDIBENZO-(B,D)PYRAN-6-ONE;3, 8-Dihydroxy-6H-benzo[c]chromen-6-one;Castoreum pigment I;Urolithin A;6H-Dibenzo(B,D)pyran-6-one, 3,8-dihydroxy-;3,8-dihydroxy-6H-dibenzopyran-6-one);urolithin-A(UA
• CAS NO: 1143-70-0
• Molecular Formula: C₁₃H₈O₄
• Molecular Weight: 228.2002
• EINECS: 1592732-453-0
• Product Categories: novel chemicals
• Mol File: 1143-70-0.mol
• Article Data: 32

Chemical Properties

• Melting Point: 340-345 °C
• Boiling Point: 527.9 °C at 760 mmHg
• Flash Point: 214.2 °C
• Appearance: /
• Density: 1.516 g/cm³
• Vapor Pressure: 9.24E-12mmHg at 25°C
• Refractive Index: 1.717
• Storage Temp.: 2-8°C
• Solubility: DMSO (Slightly), Methanol (Very Slightly)
• PKA: 9.07±0.20(Predicted)
• CAS DataBase Reference: 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one(CAS DataBase Reference)
• NIST Chemistry Reference: 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one(1143-70-0)
• EPA Substance Registry System: 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one(1143-70-0)

Safety Data

• Hazardous Substances Data: 1143-70-0(Hazardous Substances Data)

Usage

Description

Urolithin A is a metabolite of ellagic acid. It is produced by the body after you ingest compounds found in particularly high concentration in pomegranates (particularly the bitter components such as the skin and seeds) and can help recycle defective mitochondria. Since it is a metabolite that results from the transformation of the tannins in pomegranate by gut bacteria, it can be classified as a postbiotic.It has been demonstrated to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging.

Uses

Urolithin A is a major metabolite of ellagitannin and exhibits anti-inflammatory and antioxidant properties.

Definition

ChEBI: Urolithin A is a member of coumarins. It has a role as a geroprotector.

Preparation

2-bromo-5-methoxybenzoic acid is coupled with resorcinol to yield the intermediate “methoxy” product (Intermediate A), which is then isolated via filtration and dried for use in step 2. The solvent methanol is utilized in this step.the intermediate product, "Intermediate A", is treated with the Lewis acid, AlCl3, in order to obtain a crude urolithin A. The ether cleavage of Intermediate A is accomplished by activation of the methyl ether through the addition of the Lewis acid, AlCl3, in toluene. The activated species is then hydrolyzed by the addition of water. Following hydrolysis, the crude product is filtered and dried.crude urolithin A is dissolved in dimethyl sulfoxide (DMSO) for a polish filtration and subsequently precipitated from this DMSO solution by the addition of water. The filter cake is rinsed by water, followed by methanol. The raw urolithin A is then triturated with acetic acid (HOAc) to further purify the product and then collected by filtration. Following filtration, the purified product is rinsed with HOAc followed by tert-butyl-methyl ether (TBME), then dried to yield the final product, urolithin A.Synthesis of Urolithin A

benefits

As you age, ATP production begins to put strain on your mitochondria, and eventually, energy output falls. But when exposed to urolithin A, these failing mitochondria are broken down and eliminated (very similar to taking out the trash!) to make room for new, properly functioning mitochondria to grow.Ellagitannins and punicalagins are two natural polyphenols found in pomegranates. They have been shown to have anti-inflammatory and anticancer effects, but once metabolized by gut bacteria, they also produce urolithin A in the digestive tract. So supplementation with pomegranate extract, along with specific bacterial species (probiotics) that can help the pomegranate compounds to produce urolithin A, can be an effective approach to maintaining healthy mitochondria.

Biochem/physiol Actions

Urolithin A is a natural product with antiproliferative and antioxidant activity. Urolithin A is formed by metabolism from polyphenols found in some nuts and fruits, particularly pomegranates. Urolithin A has been shown to cross the blood brain barrier, and may have neuroprotective effects against Alzheimer′s Disease.

Side effects

The urolithin A supplementation was generally well-tolerated, although there were a few side effects recorded: increased lipids, triglycerides, LDL cholesterol, and chest pains.(But there was very little difference between the placebo group — where similar adverse effects were recorded — and the intervention group.) Most of these were mild and only one person withdrew from the trial due to side effects.

Metabolism

lt appears that the majority of ingested ellagitannins and EA are metabolized by thegut microbiota into a variety of urolithins. Urolithins are dibenzopyran-6-one derivatives that are produced from EA through the loss of one of the two lactonespresent in EA and then by successive removal of hydroxyl groups.Urolithin D isproduced first，followed sequentially by urolithin C, urolithin A, and urolithin B.Urolithins appear in the circulatory system almost exclusively as glucuronide,sulfateand methylated forms as a result of phase Il metabolism after absorption in the colonand passage through the liver.

Clinical claims and research

Some of the earliest research on urolithin A was performed on C. elegans worms, which experienced a 45 percent longer life span than worms not given the compound. Rodents given urolithin A experienced markedly improved muscular function and clearance of damaged mitochondria. Compared to a control group, these rodents showed a 57 to 65 percent increase in exercise capacity, 42 percent increase in running endurance, and a 9 percent increase in grip strength—all markers that correlate with longevity.In addition, researchers have exposed colon cancer stem cells to a mixture containing urolithin A and found it to be effective at inhibiting the number and size of colon cancer stem cells and also in inhibiting the activity of aldehyde dehydrogenase, a marker of resistance to chemotherapy. Urolithin A can also cross the blood-brain barrier to protect against neurotoxicity and amyloid plaque accumulation.

InChI:InChI=1/C13H8O4/c14-7-1-3-9-10-4-2-8(15)6-12(10)17-13(16)11(9)5-7/h1-6,14-15H

Upstream product

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• 156206-33-6 2,2'-dihydroxy-4,4'-dimethoxybiphenyl 
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• 183474-19-3 4-methoxy-2-benzyloxybenzeneboronic acid 
• 150356-67-5 1-bromo-4-methoxy-2-(phenylmethoxy)benzene 
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• 955929-53-0 (4-{[tert-butyl(dimethyl)silyl]oxy}-2-methoxyphenyl)boronic acid 
• 58380-11-3 2-bromo-5-hydroxybenzoic acid 
• 108-46-3 recorcinol 
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• 1459238-39-1 methyl 2'-bromo-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate 

Downstream Products

• 713520-58-2 3,8-di(t-butyldimethylsilyloxy)-6-[4-[2-(1-piperidino)ethoxy]-phenyl]dibenzo[b,d]pyran 
• 713520-69-5 3,8-di(t-butyldimethylsilyloxy)-6-[4-[2-(1-pyrrolidino)ethoxy]-phenyl]dibenzo[b,d]pyran 
• 713520-51-5 3,8-di(t-butyldimethylsilyloxy)-6-phenoxydibenzo[b,d]pyran 
• 165393-06-6 urolithin C 
• 165393-08-8 3,8-diketodibenzo-α-pyrone 

Relevant articles and documents

Urolithins, intestinal microbial metabolites of pomegranate ~ellagitannins, exhibit potent antioxidant activity in a cell-based assay

Many health benefits of pomegranate products have been attributed to the potent antioxidant action of their tannin components, mainly punicalagins and ellagic acid. While moving through the intestines, ellagitannins are metabolized by gut bacteria into urolithins that readily enter systemic circulation. In this study, the antioxidant properties of seven urolithin derivatives were evaluated in a cell-based assay. This method is biologically more relevant because it reflects bioavailability of the test compound to the cells, and the antioxidant action Is determined in the cellular environment. Our results showed that the antioxidant activity of urolithins was correlated with the number of hydroxy groups as well as the lipophilicity of the molecule. The most potent antioxidants are urolithins C and D with IC50 values of 0.16 and 0.33 μM, respectively, when compared to IC50 values of 1.1 and 1.4 μM of the parent ellagic acid and punicalagins, respectively. The dihydroxylated urolithin A showed weaker antioxidant activity, with an IC 50 value 13.6 μM, however, the potency was within the range of urolithin A plasma concentrations. Therefore, products of the intestinal microbial transformation of pomegranate ellagitannins may account for systemic antioxidant effects.

Urolithin as a Converging Scaffold Linking Ellagic acid and Coumarin Analogues: Design of Potent Protein Kinase CK2 Inhibitors

Casein kinase2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (Ki=20nM) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, Ki=60nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithinA as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a Ki value of 7nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments. Two become one: Comparing the crystallographic binding modes of ellagic acid (red) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC; blue), an X-ray structure-driven merging approach to the design of novel casein kinase2 (CK2) inhibitors was taken. Using this strategy, a potent and selective urolithin derivative, 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one was identified, which exhibits a Ki value of 7nM against CK2.

Urolithin and reduced urolithin derivatives as potent inhibitors of tyrosinase and melanogenesis: Importance of the 4-substituted resorcinol moiety

We previously reported (E)-β-phenyl-α,β-unsaturated carbonyl scaffold ((E)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosi-nase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyro-sinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (E)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds 1c (IC50 = 18.09 ± 0.25 μM), 1h (IC50 = 4.14 ± 0.10 μM), and 2a (IC50 = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC50 = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhi-bition.

Synthetic method of urolithin A

The invention discloses a synthetic method of urolithin A. The synthetic method comprises the steps of coupling, primary protective group removal, sulfonylation, carboxylation-lactonization, secondaryprotective group removal and the like. The method provided by the invention is a novel method for synthesizing urolithin A, the raw material is cheap and easy to obtain, the used reaction reagent issmall in environmental pollution and simple in route, and the method can be used for large-scale preparation of urolithin A.

Urolithins as immune response enhancers

Disclosed are compounds for use in raising an immune response to an antigen and/or enhancing, modulating or augmenting an immune response to an antigen. Particularly the use of urolithins. The invention also relates to immune enhancers comprising urolithins, methods of using such immune enhancers and processes for the preparation of such immune enhancers. The invention also relates to the use of urolithins in methods for modulating stem cell function, for example, enhancing stem cell numbers, promoting stem cell regeneration and promoting stem cell differentiation.