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

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

Uses

Used in Anti-aging Applications:
3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one is used as a geroprotector for its potential to promote healthy aging and extend lifespan. Its role as a geroprotector is attributed to its ability to stimulate mitophagy, a process that helps recycle defective mitochondria, which is crucial for maintaining cellular health and function.
Used in Pharmaceutical Industry:
3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one is used as a pharmaceutical candidate for its potential therapeutic applications. Its unique structure and properties make it a promising compound for the development of new drugs targeting various health conditions and diseases.
Used in Nutraceutical Industry:
3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one can be used as a nutraceutical ingredient for its health-promoting properties. Its potential role in promoting healthy aging and extending lifespan makes it a valuable addition to dietary supplements and functional foods.

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

• 133730-29-7 N,N-Diethyl-2',4,4'-trimethoxy-2-biphenylcarboxamide 
• 62924-93-0 N,N-diethyl-3-methoxybenzamide 
• 35233-17-1 3-hydroxy-8-methoxy-6H-dibenzo-[b,d]pyran-6-one 
• 22921-68-2 2-bromo-5-methoxy-benzoic acid 
• 108-46-3 recorcinol 
• 58380-11-3 2-bromo-5-hydroxybenzoic acid 
• 1379680-46-2 2,2'-bis[(trifluoromethanesulfonyl)oxy]-4,4'-dimethoxybiphenyl 
• 156206-33-6 2,2'-dihydroxy-4,4'-dimethoxybiphenyl 
• 1379680-45-1 2,2'-bis(benzyloxy)-4,4'-dimethoxybiphenyl 
• 183474-19-3 4-methoxy-2-benzyloxybenzeneboronic acid 
• 150356-67-5 1-bromo-4-methoxy-2-(phenylmethoxy)benzene 
• 235091-20-0 4-(benzyloxy)-1-bromo-2-(methoxymethoxy)benzene 
• 955929-53-0 (4-{[tert-butyl(dimethyl)silyl]oxy}-2-methoxyphenyl)boronic acid 

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 C, a gut metabolite of ellagic acid, induces apoptosis in PC12 cells through a mitochondria-mediated pathway

Urolithins (Uros), metabolites of ellagitannins (ET) and ellagic acid (EA) produced by gut microbiota, showed better bioavailability and extensive bioactivity, and were considered as the active compounds responsible for the health benefits exerted by ET-containing foodstuffs. Here, we chemically synthesized three Uros including Uros A, B, and C and compared their anti-proliferative activities with that of EA in PC12 cells. MTT assay showed that EA significantly promoted, while Uros significantly inhibited the proliferation of PC12 cells, among which UroC showed the strongest anti-proliferation. UroC treatment actively increased the lactate dehydrogenase (LDH) release and lipid peroxidation malondialdehyde (MDA), stimulated reactive oxygen species (ROS) formation and mitochondrial membrane depolarization, and caused calcium dyshomeostasis. Furthermore, flow cytometry analysis showed that UroC treatment induced apoptosis and S phase cell cycle arrest with increasing UroC concentrations. Consequently, UroC also induced imbalance in the Bcl-2/Bax ratio, which triggered the caspase cascade, thereby shifting the balance in favor of apoptosis, as evidenced by western blotting and real-time PCR. These observations indicated that UroC possessed significantly different anti-proliferation activities from EA, and actively induced cell apoptosis through a mitochondria-mediated pathway.

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.

Gut Microbiota conversion of dietary ellagic acid into bioactive phytoceutical urolithin a inhibits heme peroxidases

Numerous studies signify that diets rich in phytochemicals offer many beneficial functions specifically during pathologic conditions, yet their effects are often not uniform due to interindividual variation. The host indigenous gut microbiota and their modifications of dietary phytochemicals have emerged as factors that greatly influence the efficacy of phytoceutical- based intervention. Here, we investigated the biological activities of one such active microbial metabolite, Urolithin A (UA or 3,8-dihydroxybenzo[c]chromen-6-one), which is derived from the ellagic acid (EA). Our study demonstrates that UA potently inhibits heme peroxidases i.e. myeloperoxidase (MPO) and lactoperoxidase (LPO) when compared to the parent compound EA. In addition, chrome azurol S (CAS) assay suggests that EA, but not UA, is capable of binding to Fe3+, due to its catechol-like structure, although its modest heme peroxidase inhibitory activity is abrogated upon Fe3+-binding. Interestingly, UA-mediated MPO and LPO inhibition can be prevented by innate immune protein human NGAL or its murine ortholog lipocalin 2 (Lcn2), implying the complex nature of host innate immunitymicrobiota interactions. Spectral analysis indicates that UA inhibits heme peroxidase-catalyzed reaction by reverting the peroxidase back to its inactive native state. In support of these in vitro results, UA significantly reduced phorbol myristate acetate (PMA)-induced superoxide generation in neutrophils, however, EA failed to block the superoxide generation. Treatment with UA significantly reduced PMA-induced mouse ear edema and MPO activity compared to EA treated mice. Collectively, our results demonstrate that microbiotamediated conversion of EA to UA is advantageous to both host and microbiota i.e. UA-mediated inhibition of pro-oxidant enzymes reduce tissue inflammation, mitigate non-specific killing of gut bacteria, and abrogate iron-binding property of EA, thus providing a competitive edge to the microbiota in acquiring limiting nutrient iron and thrive in the gut.

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.

Synthesis, Characterization, Molecular Docking, and Biological Activities of Some Natural and Synthetic Urolithin Analogs

Urolithins (that is, hydroxy substituted benzo[c]chromen-6-one derivatives) are formed within the gastrointestinal tract following to the exposure to various ellagitannin rich diet, particularly involving pomegranate, nuts, and berries. Regarding the bioavailability deficiency of ellagitannins, the biological activities obtained through the extracts of these dietaries are attributed to the urolithin compounds, since they are bioavailable. Particularly, there are studies indicating the importance of ellagitannin-rich food for protective and alternative treatment of Alzheimer's Disease (AD). From this perspective, within this study, the major urolithins (that is, urolithins A and B), their methyl ether metabolites, as well as some synthetic urolithin analogs have been synthesized and screened for their biological activities in various enzyme inhibition (acetylcholinesterase, butyrylcholinesterase, monoamine oxidase B, cyclooxygenase 1, and cyclooxygenase 2) and antioxidant (DPPH radical scavenging) assay systems. The results pointed out the potential of urolithins to act as inhibitors on these receptors. Docking studies were also performed to investigate the possible interactions.

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.

Urolithin A and B Derivatives as ON-OFF Selective Fluorescent Sensors for Iron(III)

The detection and sensing of environmentally crucial metal ions has always been of great significance in various fields such as biological and environmental cycles. Our previous studies have indicated a new coumarin based lactone, Urolithin B (i.e., 3-Hydroxy[c]chromen-6-one) as a potent fluorescent probe for the selective detection of Iron (III). In order to question the extension of this application to other urolithins, we have synthesized the major urolithins that humans are exposed to through regular diet. Following the structure identifying studies, the compounds were tested in fluorescence titration to investigate their interaction with various metals. The results have indicated that each title compound is selective to interact with Iron (III) in ON-OFF mode, independent from the presence of another metal. Similar to the previous findings, the Job’s plots displaying the ratio of complex formation 3:2 UROs:Fe3+ have indicated the significance of the lactone group solely.

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.

UROLITHINS-CONTAINING AQUEOUS SOLUTION, DRIED SOLID COMPOSITION THEREOF AND PRODUCTION METHOD THEREFOR, AND UROLITHINS STABILIZING METHOD

A urolithin-containing aqueous solution containing urolithin and collagen, a dried solid composition thereof, methods for producing these, and a stabilization method for urolithin.