4-Methylesculetin

J Toxicol Environ Health A. 2015;78(2):109-18.

In vitro assessment of mutagenic and genotoxic effects of coumarin derivatives 6,7-dihydroxycoumarin and 4-methylesculetin.[Pubmed: 25424619]

Coumarins are naturally occurring compounds, widely distributed throughout the plant kingdom (Plantae), and possess important pharmacological properties, including inhibition of oxidative stress. In this context, newly synthesized coumarin compounds are being produced due to their potent antioxidant activities. Therefore, the aim of the present study was to determine the in vitro cytotoxic, mutagenic, and genotoxic effects of 6,7-dihydroxycoumarin (6,7-HC) and 4-Methylesculetin (4-ME) using the Salmonella/microsome test and in cultured human lymphocytes the comet assay and micronucleus test.
METHODS AND RESULTS:
The three coumarin derivatives concentrations evaluated in comet and MN assays were 2, 8, and 32 μg/mL, selected through a preliminary trypan blue-staining assay. In the Ames test, the 5 concentrations tested were 62.5, 125, 250, 500, and 750 μg/plate. Positive (methyl methane-sulfonate, MMS) and negative (dimethyl sulfoxide, DMSO) control groups were also included in the analysis.
CONCLUSIONS:
Our results showed that 4-ME induced greater cytotoxicity at high concentrations than 6,7-HC. In addition, both compounds were not mutagenic in the Ames test and not genotoxic or clastogenic/aneugenic in cultured human lymphocytes.

Int J Cancer. 2007 Jun 15;120(12):2704-9.

Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice.[Pubmed: 17354230 ]

We report the inhibitory effect of 4-Methylesculetin (ME), a 4-methylumbelliferone derivative, on hyaluronan (HA) synthesis by pancreatic cancer cells, and its resulting anticancer action.
METHODS AND RESULTS:
First, HA in cell culture was analyzed using competitive inhibition with hyaluronic acid-binding protein (HABP) to study HA synthesis by the human pancreatic cancer cell line KP1-NK, and cell-surface HA was visualized using a particle-exclusion assay to study the synthesis of extracellular matrix HA. We also analyzed the inhibitory effect of ME on cell adhesion and invasion, which play a role in the invasion, growth and metastasis of human pancreatic cancer. Furthermore, we examined HA in human pancreatic cancer cells transplanted into the hypodermis of nude mice to study the inhibitory effect of ME on HA synthesis. Moreover, pancreatic cancer cells were also transplanted into the abdomen of nude mice to study whether ME would have the potential to prolong the survival of patients with end-stage pancreatic cancer. ME at 10 muM did not inhibit the growth of human pancreatic cancer cells, but inhibited HA synthesis in cell culture by 40%, adhesion by 44% and invasion by 40%. ME inhibited the proliferation of subcutaneous tumors and HA synthesis (by 50%) of pancreatic cancer transplanted into the hypodermis of nude mice. ME also prolonged the survival time of nude mice bearing abdominally transplanted pancreatic cancer cells. ME inhibited pancreatic cancer growth and metastasis by inhibition of HA synthesis.
CONCLUSIONS:
These results suggest that ME may prolong the survival time of patients with end-stage pancreatic cancer.

Chem Biol Interact. 2018 Jan 25;280:59-63.

4-methylesculetin, a coumarin derivative, ameliorates dextran sulfate sodium-induced intestinal inflammation.[Pubmed: 29217385 ]

4-Methylesculetin is one of the coumarin derivatives with great anti-oxidant and anti-inflammatory activities. Recent studies have shown that 4-Methylesculetin has a promising potentiality to treat inflammatory diseases, especially those related to reactive oxygen species, as inflammatory bowel disease.
METHODS AND RESULTS:
Based on this, the present study aims to investigate the intestinal anti-inflammatory activity of 4-Methylesculetin in dextran sulfate sodium (DSS) model. For this purpose, mice received DSS 5% for 5 days followed by 2 days of filtered tap water. Treated groups received orally 5 or 25 mg/kg of 4-Methylesculetin daily since the first day. Macroscopic, microscopic and biochemical parameters were evaluated. 4-Methylesculetin (25 mg/kg) improved microscopic parameters, decreased MPO activity, reduced the colonic levels of IL-6 and counteracted GSH depletion when compared with DSS-control group.
CONCLUSIONS:
Our results show the intestinal anti-inflammatory activity of 4-Methylesculetin in DSS model, which is related to its antioxidant and anti-inflammatory properties. This way, 4-Methylesculetin, is a new potential compound for treatment of both types of IBD.

J Appl Toxicol. 2014 Jan;34(1):33-9.

Absence of genotoxic effects of the coumarin derivative 4-methylesculetin in vivo and its potential chemoprevention against doxorubicin-induced DNA damage.[Pubmed: 23047850 ]

4-Methylesculetin (4-ME) is a synthetic derivative of coumarin that displays a potent reactive oxygen species (ROS) scavenger and metal chelating agent and therefore has been produced to help reduce the risk of human disease. The main objective of this study was to investigate the in vivo genotoxicity of 4-ME and initially to verify its potential antigenotoxicity on doxorubicin (DXR)-induced DNA damage.
METHODS AND RESULTS:
Different doses of 4-ME (500, 1000 and 2000 mg kg(-1) body weight) were administered by gavage only or with a simultaneous intraperitoneal (i.p.) injection of DXR (80 mg kg(-1)). The following endpoints were analyzed: DNA damage in peripheral blood, liver, bone marrow, brain and testicle cells according to an alkaline (pH > 13) comet assay and micronucleus induction in bone marrow cells. Cytotoxicity was assessed by scoring polychromatic (PCE) and normochromatic (NCE) erythrocytes (PCE/NCE ratio).
CONCLUSIONS:
No differences were observed between the negative control and the groups treated with a 4-ME dose for any of the endpoints analyzed, indicating that it lacks genotoxic and cytotoxic effects. Moreover, 4-ME demonstrated protective effects against DXR-induced DNA damage at all tested doses and in all analyzed cell types, which ranged from 34.1% to 93.3% in the comet assay and 54.4% to 65.9% in the micronucleus test.

Biochimie. 2013 Jun;95(6):1326-35.

Antiarthritic and antiinflammatory propensity of 4-methylesculetin, a coumarin derivative.[Pubmed: 23485680]

Coumarins are a group of natural compounds widely distributed in plants. Of late, coumarins and their derivatives have grabbed much attention from the pharmacological and pharmaceutical arena due to their broad range of therapeutical qualities. A coumarin derivative 4-Methylesculetin (4-ME) has known to possess effective antioxidant and radical-scavenging properties. Recently they have also shown to down regulate nuclear factor-kappa B (NF-κB) and protein kinase B (Akt) that play a vital role in inflammation and apoptosis.
METHODS AND RESULTS:
In view of this, the present study investigated the anti-arthritic potentiality of 4-ME by assessing its ability to inhibit cartilage and bone degeneration, inflammation and associated oxidative stress. Arthritis being a debilitating joint disease, results in the deterioration of extracellular matrix (ECM) of cartilage and synovium. Participation of both enzymatic and non-enzymatic factors in disease perpetuation is well documented. The present study demonstrated the mitigation of augmented serum levels of hyaluronidase and matrix metalloproteinases (MMP-13, MMP-3 and MMP-9) responsible for cartilage degeneration by 4-ME. It also protected bone resorption by reducing the elevated levels of bone-joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Further, 4-ME significantly ameliorated the upregulated non-enzymatic inflammatory markers like TNF-α, IL-1β, IL-6, COX-2 and PGE2. Besides, 4-ME effectively stabilized the arthritis-induced oxidative stress by restoring the levels of reactive oxygen species, lipid and hydro peroxides and antioxidant enzymes such as superoxide dismutase, catalase and glutathione-S-transferase.
CONCLUSIONS:
Thus, the study suggests that 4-ME could be an effective agent to treat arthritis and associated secondary complications like oxidative stress.