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.

Reagent-induced asymmetric induction in addition reaction of reduced glutathione onto bis-Mannich chalcones.

The stereochemistry of non-enzyme catalyzed nucleophilic addition of GSH to 4'-hydroxychalcone 1 and its bis-Mannich derivative 2 was investigated at different pH values (pH 3.2, 6.1, 7.4, and 8.0). The stereochemical outcome of the reactions was evaluated by HPLC-UV-Vis method. Under strongly acidic conditions (pH 3.2), an unexpected diastereoselective addition of GSH onto the bis-Mannich derivative 2 was observed. Such a selectivity could not be observed in the similar reaction of 2 with N-acetylcysteine. The observed stereoselectivity can be rationalized by ion-pair formation between the protonated Mannich nitrogens and the deprotonated GSH(glutamate)-carboxylate. To the best of our knowledge, this is the first example of reagent-induced asymmetric induction in Michael-type additions of thiols.

Absence of genotoxic effects of the chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one) and its potential chemoprevention against DNA damage using in vitro and in vivo assays.

The chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methylphenyl)-prop-2-en-1-one), or 2HMC, displays antileishmanial, antimalarial, and antioxidant activities. The aim of this study was to investigate the cytotoxic, genotoxic, mutagenic, and protective effects of 2HMC using the Ames mutagenicity test, the mouse bone marrow micronucleus test, and the comet assay in mice. In the assessment using the Ames test, 2HMC did not increase the number of His+ revertants in Salmonella typhimurium strains, demonstrating lack of mutagenicity. 2HMC showed no significant increase in micronucleated polychromatic erythrocyte frequency (MNPCE) in the micronucleus test, or in DNA strand breaks using the comet assay, evidencing absence of genotoxicity. Regarding cytotoxicity, 2HMC exhibited moderate cytotoxicity in mouse bone marrow cells by micronucleus test. 2HMC showed antimutagenic action in co-administration with the positive controls, sodium azide (SA) and 4-nitroquinoline-1-oxide (4NQO), in the Ames test. Co-administered and mainly pre-administered with cyclophosphamide (CPA), 2HMC caused a decrease in the frequency of MNPCE using the micronucleus test and in DNA strand breaks using the comet assay. Thus, 2HMC exhibited antimutagenic and antigenotoxic effects, displaying a DNA-protective effect against CPA, SA, and 4NQO carcinogens. In conclusion, 2HMC presented antimutagenic, antigenotoxic and moderate cytotoxic effects; therefore it is a promising molecule for cancer prevention.

Genotoxic, Cytotoxic, Antigenotoxic, and Anticytotoxic Effects of Sulfonamide Chalcone Using the Ames Test and the Mouse Bone Marrow Micronucleus Test.

Chalcones present several biological activities and sulfonamide chalcone derivatives have shown important biological applications, including antitumor activity. In this study, genotoxic, cytotoxic, antigenotoxic, and anticytotoxic activities of the sulfonamide chalcone N-{4-[3-(4-nitrophenyl)prop-2-enoyl]phenyl} benzenesulfonamide (CPN) were assessed using the Salmonella typhimurium reverse mutation test (Ames test) and the mouse bone marrow micronucleus test. The results showed that CPN caused a small increase in the number of histidine revertant colonies in S. typhimurium strains TA98 and TA100, but not statistically significant (p > 0.05). The antimutagenicity test showed that CPN significantly decreased the number of His+ revertants in strain TA98 at all doses tested (p < 0.05), whereas in strain TA100 this occurred only at doses higher than 50 µg/plate (p < 0.05). The results of the micronucleus test indicated that CPN significantly increased the frequency of micronucleated polychromatic erythrocytes (MNPCE) at 24 h and 48 h, revealing a genotoxic effect of this compound. Also, a significant decrease in polychromatic/normochromatic erythrocyte ratio (PCE/NCE) was observed at the higher doses of CPN at 24 h and 48 h (p < 0.05), indicating its cytotoxic action. CPN co-administered with mitomycin C (MMC) significantly decreased the frequency of MNPCE at almost all doses tested at 24 h (p < 0.05), showing its antigenotoxic activity, and also presented a small decrease in MNPCE at 48 h (p > 0.05). Additionally, CPN co-administered with MMC significantly increased PCE/NCE ratio at all doses tested, demonstrating its anticytotoxic effect. In summary, CPN presented genotoxic, cytotoxic, antigenotoxic, and anticytotoxic properties.