Protective effects and DNA repair induction of a coumarin-chalcone hybrid against genotoxicity induced by mutagens.

Coumarins and chalcones are compounds widely found in plants or obtained by synthetic methods which possess several biological properties including antioxidant, anti-inflammatory, and antitumor effects. A series of coumarin-chalcone hybrids were synthesized to improve their biological actions and reduce potential adverse effects. Considering the applications of these molecules, a coumarin-chalcone hybrid [7-methoxy-3-(E)-3-(3,4,5-trimethoxyphenyl) acryloyl-2 H-chromen-2-one] (4-MET) was synthesized and the genotoxic, cytotoxic, and protective effects assessed against damage induced by different mutagens. First, in silico tools were used to predict biological activity of 4-MET which indicated a chemopreventive potential. Subsequently, the genotoxic/antigenotoxic activities of 4-MET were determined both in vitro (Ames test) and in vivo (micronucleus (MN) test and comet assay). In addition, molecular docking simulations were performed between 4-MET and glutathione reductase, an important cellular detoxifying enzyme. Our results indicated that 4-MET was not mutagenic in the Ames test; however, when co-treated with sodium azide or 4-nitroquinoline 1-oxide (4-NQO), 4-MET significantly reduced the harmful actions of these mutagens. Except for a cytotoxic effect after 120 hr treatment, 4-MET alone did not produce cytotoxicity or genotoxicity in the MN test and comet assay. Nonetheless, all treatments of 4-MET with cyclophosphamide (CPA) showed a chemoprotective effect against DNA damage induced by CPA. Further, molecular docking analysis indicated a strong interaction between 4-MET and the catalytic site of glutathione reductase. These effects may be related to (1) damage prevention, (2) interaction with detoxifying enzymes, and (3) DNA-repair induction. Therefore, data demonstrated that 4-MET presents a favorable profile to be used in chemopreventive therapies.

Modulating effect of a hydroxychalcone and a novel coumarin-chalcone hybrid against mitomycin-induced genotoxicity in somatic cells of Drosophila melanogaster.

Chalcones are aromatic compounds found in plants or obtained by synthetic methods. These compounds and their derivatives have been proven to be responsible for a variety of pharmacological properties, including anti-inflammatory and anticancer activities. A second interesting class of compound are coumarins which comprises a large class of molecules derived from phenolic compounds found mainly in plants, exhibiting multiple biological activities such as antioxidant and anti-tumoral properties. Due to the relevance of these compounds, this study aimed to investigate the genotoxic/antigenotoxic effects of the chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one (2HMC) and the coumarin-chalcone hybrid [7-methoxy-3-(E)-3-(3,4,5-trimethoxyphenyl)acryloyl-2H-cromen-2-one] (4-MET) using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. To assess the mutagenic and recombinogenic activities, larvae derived from standard and high bioactivation crosses were treated with different concentrations of 2HMC (10, 50, 100 and 400 µg/mL) or 4-MET (5, 50, 100 and 400 µg/mL) for 48 h. Dimethylsulfoxide (DMSO, 0.5%) was the negative control group. The anti-recombinogenic and antimutagenic activities were assessed using larvae from both crosses co-treated with the same concentrations of 2HMC or 4-MET and mitomycin C (MMC, 0.05 mM). SMART revealed no mutagenic or recombinogenic effects since no significant increase of any category of mutant spots was observed (p > 0.05). However, both compounds reduced the frequency of all spots induced by MMC showing antimutagenic and anti-recombinogenic activities in D. melanogaster cells from both crosses. We suggest that the antimutagenic and anti-recombinogenic activities observed in our study may have been a result of the antioxidant activity of 2HMC and 4-MET.