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

ABSTRACT

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.

KEYWORDS:

• Ames test
• antigenotoxicity
• comet assay
• micronucleus test
• molecular docking

Acknowledgments

The author Elisa Flávia Luiz Cardoso Bailão was supported by Universidade Estadual de Goiás with fellowships at the PROBIP program. We would also like to thank Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) for the financial support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Supplementary material

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Additional information

Funding

This work was supported by the 01100005285Fundação de Amparo à Pesquisa do Estado de Goiás [01]; Universidade Estadual de Goias [01].This work was supported by the 01100005285Fundação de Amparo à Pesquisa do Estado de Goiás [01]; Universidade Estadual de Goias [01].