Please use this identifier to cite or link to this item: https://scidar.kg.ac.rs/handle/123456789/11974
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
Authors: Mladenović M.
Stankovic, Nevena
Matić, Sanja
Stanic J.
Mihailovic, Mirjana
Mihailovic, Vladimir
Katanić Stanković, Jelena S.
Jurić, Tatjana
Vukovic, Nenad
Journal: Biochemical Pharmacology
Issue Date: 1-Nov-2015
Abstract: © 2015 Elsevier Inc. All rights reserved. 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 O6-ethylguanine lesion which is incorporated in aberrant genotoxic G=T and T=G 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.
URI: https://scidar.kg.ac.rs/handle/123456789/11974
Type: Article
DOI: 10.1016/j.bcp.2015.08.106
ISSN: 00062952
SCOPUS: 84943457635
Appears in Collections:Faculty of Science, Kragujevac
Institute for Information Technologies, Kragujevac
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