Hymecromone (4-methylumbelliferone) is a drug used in bile therapy. It is used as choleretic and antispasmodic drugs and as a standard for the fluorometric determination of enzyme activity.
Hymecromone is a crystalline solid with a melting point of 194–195 °C. It is soluble in methanol and glacial acetic acid. |
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InChI=1S/C10H8O3/c1-6-4-10(12)13-9-5-7(11)2-3-8(6)9/h2-5,11H,1H3 |
HSHNITRMYYLLCV-UHFFFAOYSA-N |
C1=2OC(=O)C=C(C1=CC=C(C2)O)C |
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hyaluronic acid synthesis inhibitor
Any compound that inhibits one or more steps in the pathway leading to the synthesis of hyaluronic acid.
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
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7-hydroxy-4-methyl-2H-chromen-2-one
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himecromona
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ChemIDplus
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hymecromone
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KEGG DRUG
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hymecromonum
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ChemIDplus
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4-Methyl-7-hydroxycoumarin
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ChemIDplus
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4-Methylumbelliferone
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KEGG COMPOUND
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4-methylumbelliferone
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UniProt
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4-MU
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ChEBI
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7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran
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7-Hydroxy-4-methyl-2-oxo-3-chromene
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NIST Chemistry WebBook
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7-Hydroxy-4-methyl-2H-1-benzopyran-2-one
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NIST Chemistry WebBook
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7-Hydroxy-4-methylcoumarin
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ChemIDplus
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beta-Methylumbelliferone
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Hymecromone
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KEGG COMPOUND
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Imecromone
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1401
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4MU
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C03081
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KEGG COMPOUND
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CPD-182
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D00170
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KEGG DRUG
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HMDB0059622
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Hymecromone
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142217
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Reaxys Registry Number
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Reaxys
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165817
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Gmelin
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90-33-5
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KEGG COMPOUND
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90-33-5
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CAS Registry Number
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ChemIDplus
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90-33-5
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NIST Chemistry WebBook
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Qin J, Kilkus J, Dawson G (2016) The hyaluronic acid inhibitor 4-methylumbelliferone is an NSMase2 activator-role of Ceramide in MU anti-tumor activity. Biochimica et biophysica acta 1861, 78-90 [PubMed:26548718] [show Abstract] Increased synthesis of hyaluronic acid (HA) is often associated with increased metastatic potential and invasivity of tumor cells. 4-Methylumbelliferone (MU) is an inhibitor of HA synthesis, and has been studied as a potential anti-tumor drug to inhibit the growth of primary tumors and distant metastasis of tumor cells. Although several studies reported that the anticancer effects of MU are mediated by inhibition of HA signaling, the mechanism still needs to be clarified. In a previous study we demonstrated the regulation of HA synthesis by ceramide, and now show how MU activated neutral sphingomyelinase2 (NSMase2) generates ceramides and mediates MU induced inhibition of HA synthesis, cell migration and invasion, and apoptosis of tumor cells. Using a HA enriched mouse oligodendroglioma cell line G26-24 we found that MU elevated the activity of NSMase2 and increased ceramide levels, which in turn increased phosphatase PP2A activity. Further, the activated PP2A reduced phosphorylation of Akt, decreased activities of HA synthase2 (HAS2) and calpains, and inhibited both the synthesis of HA, and the migration and invasion of G26-24 tumor cells. In addition, MU mediated ceramide stimulated activation of p53 and caspase-3, reduced SIRT1 expression and decreased 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, suggesting that ceramides play a key role in the ability of a tumor to become aggressively metastatic and grow. | Fang Y, Wang H, Zhu W, Wang L, Liu H, He Y, Xu X, Yin W, Sima Y, Xu S (2014) Antioxidative capacity in the fat body of Bombyx mori is increased following oral administration of 4-methylumbelliferone. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 159, 31-37 [PubMed:24080584] [show Abstract] Plant sources of umbelliferones have tumor-inhibitory effects at the cellular level. However, their physiological functions in animals are largely unresolved. In this study, we provide evidence to show that 4-methylumbelliferone (4-MU) participates in the regulation of antioxidative capacity in the fat body of Bombyx mori, a tissue similar to mammalian liver in this model invertebrate. Larvae (3rd day of the 5th instar) were orally exposed to 4 mM 4-MU, an umbelliferone, which swiftly induced the generation of a large number of ROS (e.g. H2O2 increased 6 to 8-fold), and 4-MU was detected in the fat body 8 min after administration. In addition, the activities of CAT and GPx were up-regulated 4 to 11-fold and 2 to 16-fold, respectively, and were helpful in defending fat body cells against oxidative injury in combination with NADPH. Furthermore, significant increases in the contents of T-AOC (up to approx. 2-fold), antioxidants of ASAFR (by 2 to 4-fold) and GSH were detected. | Saito T, Tamura D, Nakamura T, Makita Y, Ariyama H, Komiyama K, Yoshihara T, Asano R (2013) 4-methylumbelliferone leads to growth arrest and apoptosis in canine mammary tumor cells. Oncology reports 29, 335-342 [PubMed:23124556] [show Abstract] Hyaluronan (HA), a major component of the extracellular matrix (ECM), is synthesized by HA synthase (HAS) 1, HAS2 and HAS3 and is intricately involved in cell growth and metastasis. The HA synthesis inhibitor 4-methylumbelliferone (4-MU) has been reported to exhibit anticancer properties in various types of malignant tumors. However, the underlying mechanisms at the molecular and cellular levels remain unclear. In this study, to establish an animal model for studying the function of HA in human breast cancer, we investigated the antitumor effects of 4-MU using canine mammary tumor (CF33) cells. First, we investigated the effects of 4-MU on HA production in CF33 cells. Quantitative analysis of HA in culture media showed that 4-MU inhibited HA synthesis, accompanied by downregulation of HAS2 mRNA levels, in a dose-dependent manner at 24-72 h. Additionally, we observed a 4-MU-mediated decrease in the extent of the cell-associated HA matrix. We examined the effect of 4-MU on cell growth and apoptosis in CF33 cells. 4-MU markedly inhibited cell proliferation and induced apoptosis in CF33 cells. In particular, our experiments showed that the mechanism of 4-MU-induced apoptosis in CF33 cells involved increased levels of expression of pro-apoptotic BAX mRNA and protein molecules. These data suggest that 4-MU may be a candidate therapeutic agent for the treatment of canine mammary tumors. Furthermore, this study provides the first indication that the canine mammary tumor may be a suitable model for comparative study of the function of HA in human breast cancer. | Benitez A, Yates TJ, Shamaldevi N, Bowen T, Lokeshwar VB (2013) Dietary supplement hymecromone and sorafenib: a novel combination for the control of renal cell carcinoma. The Journal of urology 190, 285-290 [PubMed:23228386] [show Abstract]
PurposeCurrent treatments for metastatic renal cell carcinoma do not extend survival beyond a few months. Sorafenib is a targeted drug approved for metastatic renal cell carcinoma but it has modest efficacy. Hymecromone is a nontoxic dietary supplement with some antitumor activity at high doses of 450 to 3,000 mg per day. Hymecromone inhibits the synthesis of hyaluronic acid, which promotes tumor growth and metastasis. We recently noted that the hyaluronic acid receptors CD44 and RHAMM are potential predictors of metastatic renal cell carcinoma. In the current study we examined the antitumor properties of hymecromone, sorafenib and the combination in renal cell carcinoma models.Materials and methodsUsing proliferation, clonogenic and apoptosis assays, we examined the effects of hymecromone (0 to 32 μg/ml), sorafenib (0 to 3.2 μg/ml) and hymecromone plus sorafenib in Caki-1, 786-O, ACHN and A498 renal cell carcinoma cells, and HMVEC-L and HUVEC endothelial cells. A Boyden chamber was used for motility and invasion assays. Apoptosis indicators, hyaluronic acid receptors, epidermal growth factor receptor and c-Met were evaluated by immunoblot. The efficacy of hymecromone, sorafenib and hymecromone plus sorafenib was assessed in the sorafenib resistant Caki-1 xenograft model.ResultsHymecromone plus sorafenib synergistically inhibited proliferation (greater than 95%), motility/invasion (65%) and capillary formation (76%) in renal cell carcinoma and/or endothelial cells, and induced apoptosis eightfold (p <0.001). Hymecromone plus sorafenib inhibited hyaluronic acid synthesis and adding hyaluronic acid reversed the cytotoxicity of hymecromone plus sorafenib. Hymecromone plus sorafenib up-regulated pro-apoptotic indicators and down-regulated Mcl-1, CD44, RHAMM, phospho-epidermal growth factor receptor and phospho-cMet. In all assays hymecromone and sorafenib alone were ineffective. Oral administration of hymecromone (50 to 200 mg/kg) plus sorafenib (30 mg/kg) eradicated Caki-1 tumor growth without toxicity. Hymecromone and sorafenib alone were ineffective.ConclusionsTo our knowledge this is the first study to show that the combination of sorafenib and the nontoxic dietary supplement hymecromone is highly effective for controlling renal cell carcinoma. | Lokeshwar VB, Lopez LE, Munoz D, Chi A, Shirodkar SP, Lokeshwar SD, Escudero DO, Dhir N, Altman N (2010) Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer research 70, 2613-2623 [PubMed:20332231] [show Abstract] 4-Methylumbelliferone (4-MU) is a hyaluronic acid (HA) synthesis inhibitor with anticancer properties; the mechanism of its anticancer effects is unknown. We evaluated the effects of 4-MU on prostate cancer cells. 4-MU inhibited proliferation, motility, and invasion of DU145, PC3-ML, LNCaP, C4-2B, and/or LAPC-4 cells. At IC(50) for HA synthesis (0.4 mmol/L), 4-MU induced >3-fold apoptosis in prostate cancer cells, which could be prevented by the addition of HA. 4-MU induced caspase-8, caspase-9, and caspase-3 activation, PARP cleavage, upregulation of Fas-L, Fas, FADD and DR4, and downregulation of bcl-2, phosphorylated bad, bcl-XL, phosphorylated Akt, phosphorylated IKB, phosphorylated ErbB2, and phosphorylated epidermal growth factor receptor. At IC(50), 4-MU also caused >90% inhibition of NF-kappaB reporter activity, which was prevented partially by the addition of HA. With the exception of caveolin-1, HA reversed the 4-MU-induced downregulation of HA receptors (CD44 and RHAMM), matrix-degrading enzymes (MMP-2 and MMP-9), interleukin-8, and chemokine receptors (CXCR1, CXCR4, and CXCR7) at the protein and mRNA levels. Expression of myristoylated-Akt rescued 4-MU-induced apoptosis and inhibition of cell growth and interleukin-8, RHAMM, HAS2, CD44, and MMP-9 expression. Oral administration of 4-MU significantly decreased PC3-ML tumor growth (>3-fold) when treatment was started either on the day of tumor cell injection or after the tumors became palpable, without organ toxicity, changes in serum chemistry, or body weight. Tumors from 4-MU-treated animals showed reduced microvessel density ( approximately 3-fold) and HA expression but increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells and expression of apoptosis-related molecules. Therefore, the anticancer effects of 4-MU, an orally bioavailable and relatively nontoxic agent, are primarily mediated by inhibition of HA signaling. | Nakamura R, Kuwabara H, Yoneda M, Yoshihara S, Ishikawa T, Miura T, Nozaka H, Nanashima N, Sato T, Nakamura T (2007) Suppression of matrix metalloproteinase-9 by 4-methylumbelliferone. Cell biology international 31, 1022-1026 [PubMed:17470403] [show Abstract] OHK cells, a human lymphoma cell line, are known to produce large amounts of hyaluronan. We investigated the effect of 4-methylumbelliferone, an inhibitor of hyaluronan synthesis, on the activity of matrix metalloproteinases in OHK cells. Matrix metalloproteinase-9 was detected on gelatin zymography as the main metalloproteinase excreted into the medium of cultured OHK cells, and 4-methylumbelliferone added to the medium decreased the activity of the enzyme in a dose-dependent manner. Addition of Streptomyces hyaluronidase to the medium during cultivation did not decrease the enzyme activity. Reverse transcription-polymerase chain reaction revealed that 4-methylumbelliferone markedly decreased the level of mRNA for matrix metalloproteinase-9 in cultured OHK cells. A similar decrease of the activity of matrix metalloproteinase-9 by 4-methylumbelliferone was also observed in cultured human breast and colon carcinoma cells. These results suggest that 4-methylumbelliferone suppresses the expression of matrix metalloproteinase-9 in cultured cancer cells. | Nakamura T, Ishikawa T, Nanashima N, Miura T, Nozaka H, Nakaoka R, Sato T (2002) 4-Methylumbelliferone induces the expression of membrane type 1-matrix metalloproteinase in cultured human skin fibroblasts. Biochemical and biophysical research communications 298, 646-650 [PubMed:12419303] [show Abstract] Human skin fibroblasts were cultured in the presence of 4-methylumbelliferone, an inhibitor of hyaluronan synthesis. Gelatinolytic activity excreted in the medium was examined by zymography and gelatinase assay using a fluorogenic substrate. 4-Methylumbelliferone added to the medium activated the latent form of matrix metalloproteinase-2 in a dose- and time-dependent manner. Immunoblot analysis also showed the conversion of the latent form of matrix metalloproteinase-2 to its active form. This activation was observed even when the cells were cultured with both 4-methylumbelliferone and hyaluronan. Addition of Streptomyces hyaluronidase to the medium during cultivation did not activate the latent form of matrix metalloproteinase-2. Reverse transcription-polymerase chain reaction revealed that 4-methylumbelliferone markedly increased the level of mRNA for membrane type 1-matrix metalloproteinase, whereas levels of mRNA for matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 were little affected. These results suggest that 4-methylumbelliferone induces the expression of membrane type 1-matrix metalloproteinase, resulting in activation of matrix metalloproteinase-2, in cultured human skin fibroblasts. | Varga JM, Kalchschmid G, Klein GF, Fritsch P (1991) Mechanism of allergic cross-reactions--I. Multispecific binding of ligands to a mouse monoclonal anti-DNP IgE antibody. Molecular immunology 28, 641-654 [PubMed:1650428] [show Abstract] A recently developed solid-phase binding assay was used to investigate the specificity of ligand binding to a mouse monoclonal anti-dinitrophenyl IgE [IgE(aDNP)]. All DNP-amino acids, that were tested, inhibited the binding of radio-labeled IgE(aDNP) to DNP covalently attached to polystyrene microtiter plates; however, the concentration for 50% inhibition varied within four orders of magnitude, DNP-L-serine being the most, DNP-proline the least potent inhibitor. In addition to DNP analogues a large number (2074) of drugs and other compounds were tested for their ability to compete with DNP for the binding site of IgE(aDNP). At the concentrations used for screening 59% of the compounds had no significant inhibition; 19% inhibited the binding of IgE(aDNP) more than 50%. Several families of compounds (tetracyclines, polymyxines, phenotiazines, salicylates and quinones) of effective competitors were found. Within these families change in the functional groups attached to the "family stem" had major effects on the affinity of ligand binding. The occurrence frequencies of interactions of ligands with IgE(aDNP) is in good agreement with a semi-empirical model for multispecific antibody-ligand interactions. |
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