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

Biochemical Pharmacology
Milan MladenovićNenad Vuković

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.

References

Mar 1, 1988·Experimental Cell Research·N P SinghE L Schneider
Oct 9, 1995·International Journal of Cancer. Journal International Du Cancer·B EyminY Pommier
Mar 1, 1994·Proceedings of the National Academy of Sciences of the United States of America·J RocaJ C Wang
Jun 12, 1996·Mutation Research·M KlaudeG Ahnström
Sep 28, 1998·Biochimica Et Biophysica Acta·D A Burden, N Osheroff
Jan 5, 2000·Environmental and Molecular Mutagenesis·S Cotelle, J F Férard
Jul 25, 2000·Toxicology Letters·G Boos, H Stopper
Aug 15, 2000·Annual Review of Biophysics and Biomolecular Structure·M A Martí-RenomA Sali
Sep 10, 2003·Proceedings of the National Academy of Sciences of the United States of America·Scott ClassenJames M Berger
Mar 31, 2004·Analytical Biochemistry·Martin G RowlandsWynne Aherne
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Mar 18, 2005·Biology of Reproduction·Rémi-Martin Laberge, Guylain Boissonneault
May 19, 2005·Mutagenesis·Susanne Brendler-SchwaabGünter Speit
Aug 16, 2005·The Journal of Biological Chemistry·Hua WeiGregory L Verdine
Aug 8, 2007·Mutation Research·A Kathleen McClendon, Neil Osheroff
Feb 20, 2008·Mutagenesis·Andrew R CollinsRudolf Stetina
Apr 17, 2009·RNA·P Therese LangIrwin D Kuntz
Apr 21, 2009·Nature Reviews. Cancer·John L Nitiss
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
May 7, 2009·Nucleic Acids Research·Marc van Dijk, Alexandre M J J Bonvin
Jun 11, 2010·Chemistry & Biology·Yves PommierChristophe Marchand
Aug 13, 2010·Metallomics : Integrated Biometal Science·Joseph E Deweese, Neil Osheroff
Mar 15, 2011·British Journal of Clinical Pharmacology·John Warren
Jan 6, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Deepak GurbaniAlok Dhawan
Oct 2, 2012·Nature Structural & Molecular Biology·Bryan H SchmidtJames M Berger
Aug 24, 2013·Bioorganic & Medicinal Chemistry Letters·Timothy J MilesNeil D Pearson
Jan 29, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Nevena StankovićSlobodan Sukdolak
Feb 25, 2014·International Journal of Biological Macromolecules·Daniel AgudeloHeidar-Ali Tajmir-Riahi
May 2, 2014·Nucleic Acids Research·Marco BiasiniTorsten Schwede
Jun 6, 2014·ACS Medicinal Chemistry Letters·Sheo B SinghYasumichi Fukuda
Dec 17, 2014·Chemico-biological Interactions·Nevena StankovićSlobodan Sukdolak

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Citations

Sep 5, 2018·Cell Communication and Signaling : CCS·Yajie WangNing Wei
May 31, 2019·Journal of Mass Spectrometry : JMS·Amauri Alves SouzaMaysa Furlan

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