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Effects of Secondary Metabolites from the Fungus Septofusidium berolinense on DNA Cleavage Mediated by Human Topoisomerase IIα

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dc.contributor.author Vann, K.R.
dc.contributor.author Ekiz, G.
dc.contributor.author Zencir, Sevil
dc.contributor.author Bedir, E.
dc.contributor.author Topcu, Z.
dc.contributor.author Osheroff, N.
dc.date.accessioned 2019-08-16T13:03:53Z
dc.date.available 2019-08-16T13:03:53Z
dc.date.issued 2016
dc.identifier.issn 0893228X (ISSN)
dc.identifier.uri http://acikerisim.pau.edu.tr:8080/xmlui/handle/11499/9648
dc.description.abstract Two metabolites from the ascomycete fungus Septofusidium berolinense were recently identified as having antineoplastic activity [Ekiz et al. (2015) J. Antibiot., DOI: 10.1038/ja.2015.84]. However, the basis for this activity is not known. One of the compounds [3,6-dihydroxy-2-propylbenzaldehyde (GE-1)] is a hydroquinone, and the other [2-hydroxymethyl-3-propylcyclohexa-2,5-diene-1,4-dione (GE-2)] is a quinone. Because some hydroquinones and quinones act as topoisomerase II poisons, the effects of GE-1 and GE-2 on DNA cleavage mediated by human topoisomerase IIα were assessed. GE-2 enhanced DNA cleavage ∼4-fold and induced scission with a site specificity similar to that of the anticancer drug etoposide. Similar to other quinone-based topoisomerase II poisons, GE-2 displayed several hallmark characteristics of covalent topoisomerase II poisons, including (1) the inability to poison a topoisomerase IIα construct that lacks the N-terminal domain, (2) the inhibition of DNA cleavage when the compound was incubated with the enzyme prior to the addition of plasmid, and (3) the loss of poisoning activity in the presence of a reducing agent. In contrast to GE-2, GE-1 did not enhance DNA cleavage mediated by topoisomerase IIα except at very high concentrations. However, the activity and potency of the metabolite were dramatically enhanced under oxidizing conditions. These results suggest that topoisomerase IIα may play a role in mediating the cytotoxic effects of these fungal metabolites. © 2016 American Chemical Society.
dc.language.iso English
dc.publisher American Chemical Society
dc.relation.isversionof 10.1021/acs.chemrestox.6b00009
dc.rights info:eu-repo/semantics/openAccess
dc.subject 2 hydroxymethyl 3 propylcyclohexa 2,5 diene 1,4 dione
dc.subject 3,6 dihydroxy 2 propylbenzaldehyde
dc.subject cytotoxic agent
dc.subject dithiothreitol
dc.subject DNA topoisomerase (ATP hydrolysing) A
dc.subject DNA topoisomerase inhibitor
dc.subject drug metabolite
dc.subject etoposide
dc.subject hydroquinone derivative
dc.subject natural product
dc.subject potassium ferricyanide
dc.subject quinone derivative
dc.subject unclassified drug
dc.subject 2-hydroxymethyl-3-propylcyclohexa-2,5-diene-1,4-dione
dc.subject 3,6-dihydroxy-2-propylbenzaldehyde
dc.subject benzaldehyde derivative
dc.subject cyclohexanone derivative
dc.subject DNA binding protein
dc.subject DNA topoisomerase (ATP hydrolysing)
dc.subject DNA topoisomerase II alpha
dc.subject tumor antigen
dc.subject amino terminal sequence
dc.subject antagonist potency
dc.subject Article
dc.subject Ascomycetes
dc.subject concentration response
dc.subject controlled study
dc.subject DNA cleavage
dc.subject drug cytotoxicity
dc.subject drug efficacy
dc.subject drug mechanism
dc.subject drug potency
dc.subject filamentous fungus
dc.subject human
dc.subject nonhuman
dc.subject oxidation
dc.subject plasmid
dc.subject Septofusidium berolinense
dc.subject chemical structure
dc.subject chemistry
dc.subject fungus
dc.subject metabolism
dc.subject secondary metabolism
dc.subject Antigens, Neoplasm
dc.subject Benzaldehydes
dc.subject Cyclohexanones
dc.subject DNA Cleavage
dc.subject DNA Topoisomerases, Type II
dc.subject DNA-Binding Proteins
dc.subject Fungi
dc.subject Humans
dc.subject Molecular Structure
dc.subject Secondary Metabolism
dc.title Effects of Secondary Metabolites from the Fungus Septofusidium berolinense on DNA Cleavage Mediated by Human Topoisomerase IIα
dc.type Article
dc.relation.journal Chemical Research in Toxicology
dc.identifier.volume 29
dc.identifier.issue 3
dc.identifier.startpage 415
dc.identifier.endpage 420
dc.identifier.index Scopus
dc.identifier.index PubMed
dc.identifier.index WOS

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