title: Newly discovered chroman-2,4-diones neutralize the in vivo DNA damage induced by alkylation through the inhibition of Topoisomerase IIα: A story behind the molecular modeling approach.
abstract: Eight chroman-2,4-diones, namely 2a-h, previously investigated as anticoagulants, of which 2a and 2f as the most active, were evaluated as in vivo genotoxic agents in Wistar rat livers and kidneys using the comet assay. Compounds 2a, 2b, and 2f without genotoxic activity were applied prior to ethyl methanesulfonate (EMS) and diminished EMS-induced DNA damage according to the total score and percentage of reduction. EMS produce harmful O(6)-ethylguanine lesion which is incorporated in aberrant genotoxic GT and TG pairing after ATP-dependent DNA strand breaks have been catalyzed by rat Topoisomerase IIα (rTopIIα, EC 5.99.1.3). Therefore, the mechanism of 2a, 2b, and 2f antigenotoxic activity was investigated on the enzyme level using molecular docking and molecular dynamics simulations insamuch as it had been determined that compounds do not intercalate DNA but instead inhibit the ATPase activity. Calculations predicted that compounds inhibit ATP hydrolysis before the DNA-EMS cleavage is being catalyzed by rTopIIα, prevent EMS mutagenic and carcinogenic effects, and beside anticoagulant activity can even be applied in the cancer treatment to control the rate of anticancer alkylation drugs.
authors: Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: mmladenovic@kg.ac.rs.
authors: Milan
authors: M
authors: Mladenović
authors: Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: nevenas@kg.ac.rs.
authors: Nevena
authors: N
authors: Stanković
authors: Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: sanjamatic@kg.ac.rs.
authors: Sanja
authors: S
authors: Matić
authors: Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: stanic@kg.ac.rs.
authors: Snežana
authors: S
authors: Stanić
authors: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Serbia. Electronic address: mista@ibiss.bg.ac.rs.
authors: Mirjana
authors: M
authors: Mihailović
authors: Bioactive Natural Products Investigation, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: vladam@kg.ac.rs.
authors: Vladimir
authors: V
authors: Mihailović
authors: Bioactive Natural Products Investigation, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: jkatanic@kg.ac.rs.
authors: Jelena
authors: J
authors: Katanić
authors: Bioactive Natural Products Investigation, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: tatjanaboroja@gmail.com.
authors: Tatjana
authors: T
authors: Boroja
authors: Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: nvukovic@kg.ac.rs.
authors: Nenad
authors: N
authors: Vuković
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D056486:Chemical and Drug Induced Liver Injury; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D020552:Comet Assay; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced; D008958:Models, Molecular; D015394:Molecular Structure; D009152:Mutagenicity Tests; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000951:Antigens, Neoplasm; D002839:Chromans; D004268:DNA-Binding Proteins; D004250:DNA Topoisomerases, Type II
keywords: Chroman-2,4-diones; Comet assay; Molecular docking; Molecular dynamics; Topoisomerase IIα