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

Milan Mladenović; Nevena Stanković; Sanja Matić; Snežana Stanić; Mirjana Mihailović; Vladimir Mihailović; Jelena Katanić; Tatjana Boroja; Nenad Vuković

doi:10.1016/j.bcp.2015.08.106

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

Biochem Pharmacol. 2015 Nov 1;98(1):243-66. doi: 10.1016/j.bcp.2015.08.106. Epub 2015 Aug 28.

Authors

Milan Mladenović¹, Nevena Stanković², Sanja Matić³, Snežana Stanić⁴, Mirjana Mihailović⁵, Vladimir Mihailović⁶, Jelena Katanić⁷, Tatjana Boroja⁸, Nenad Vuković⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, PO Box 60, 34000 Kragujevac, Serbia. Electronic address: nvukovic@kg.ac.rs.

PMID: 26319574
DOI: 10.1016/j.bcp.2015.08.106

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.

Keywords: Chroman-2,4-diones; Comet assay; Molecular docking; Molecular dynamics; Topoisomerase IIα.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism
Binding Sites
Chemical and Drug Induced Liver Injury
Chromans / chemistry
Chromans / pharmacology*
Comet Assay
DNA Damage*
DNA Topoisomerases, Type II / genetics
DNA Topoisomerases, Type II / metabolism
DNA-Binding Proteins / antagonists & inhibitors*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Gene Expression Regulation, Enzymologic / drug effects
Kidney Diseases / chemically induced
Models, Molecular
Molecular Structure
Mutagenicity Tests
Protein Conformation
Rats
Rats, Wistar

Substances

Antigens, Neoplasm
Chromans
DNA-Binding Proteins
DNA Topoisomerases, Type II