Induction of unique structural changes in guanine-rich DNA regions by the triazoloacridone C-1305, a topoisomerase II inhibitor with antitumor activities
Identifieur interne : 001774 ( Main/Exploration ); précédent : 001773; suivant : 001775Induction of unique structural changes in guanine-rich DNA regions by the triazoloacridone C-1305, a topoisomerase II inhibitor with antitumor activities
Auteurs : Krzysztof Lemke [Pologne, France] ; Marcin Wojciechowski [Pologne] ; William Laine [France] ; Christian Bailly [France] ; Pierre Colson [Belgique] ; Maciej Baginski [Pologne] ; Annette K. Larsen [France] ; Andrzej Skladanowski [Pologne]Source :
- Nucleic Acids Research [ 0305-1048 ] ; 2005.
Abstract
We recently reported that the antitumor triazoloacridone, compound C-1305, is a topoisomerase II poison with unusual properties. In this study we characterize the DNA interactions of C-1305 in vitro, in comparison with other topoisomerase II inhibitors. Our results show that C-1305 binds to DNA by intercalation and possesses higher affinity for GC- than AT-DNA as revealed by surface plasmon resonance studies. Chemical probing with DEPC indicated that C-1305 induces structural perturbations in DNA regions with three adjacent guanine residues. Importantly, this effect was highly specific for C-1305 since none of the other 22 DNA interacting drugs tested was able to induce similar structural changes in DNA. Compound C-1305 induced stronger structural changes in guanine triplets at higher pH which suggested that protonation/deprotonation of the drug is important for this drug-specific effect. Molecular modeling analysis predicts that the zwitterionic form of C-1305 intercalates within the guanine triplet, resulting in widening of both DNA grooves and aligning of the triazole ring with the N7 atoms of guanines. Our results show that C-1305 binds to DNA and induces very specific and unusual structural changes in guanine triplets which likely plays an important role in the cytotoxic and antitumor activity of this unique compound.
Url:
DOI: 10.1093/nar/gki904
Affiliations:
- Belgique, France, Pologne
- Hauts-de-France, Nord-Pas-de-Calais, Île-de-France
- Lille, Paris 12
- Université Pierre-et-Marie-Curie
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Acids Res.</title><idno type="ISSN">0305-1048</idno><idno type="eISSN">1362-4962</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005">2005</date><biblScope unit="volume">33</biblScope><biblScope unit="issue">18</biblScope><biblScope unit="page" from="6034">6034</biblScope><biblScope unit="page" to="6047">6047</biblScope></imprint><idno type="ISSN">0305-1048</idno></series><idno type="istex">766E1AE927E5D6010CE2360E3D88393C24BD439B</idno><idno type="DOI">10.1093/nar/gki904</idno><idno type="local">gki904</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0305-1048</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We recently reported that the antitumor triazoloacridone, compound C-1305, is a topoisomerase II poison with unusual properties. In this study we characterize the DNA interactions of C-1305 in vitro, in comparison with other topoisomerase II inhibitors. Our results show that C-1305 binds to DNA by intercalation and possesses higher affinity for GC- than AT-DNA as revealed by surface plasmon resonance studies. Chemical probing with DEPC indicated that C-1305 induces structural perturbations in DNA regions with three adjacent guanine residues. Importantly, this effect was highly specific for C-1305 since none of the other 22 DNA interacting drugs tested was able to induce similar structural changes in DNA. Compound C-1305 induced stronger structural changes in guanine triplets at higher pH which suggested that protonation/deprotonation of the drug is important for this drug-specific effect. Molecular modeling analysis predicts that the zwitterionic form of C-1305 intercalates within the guanine triplet, resulting in widening of both DNA grooves and aligning of the triazole ring with the N7 atoms of guanines. Our results show that C-1305 binds to DNA and induces very specific and unusual structural changes in guanine triplets which likely plays an important role in the cytotoxic and antitumor activity of this unique compound.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>France</li><li>Pologne</li></country><region><li>Hauts-de-France</li><li>Nord-Pas-de-Calais</li><li>Île-de-France</li></region><settlement><li>Lille</li><li>Paris 12</li></settlement><orgName><li>Université Pierre-et-Marie-Curie</li></orgName></list><tree><country name="Pologne"><noRegion><name sortKey="Lemke, Krzysztof" sort="Lemke, Krzysztof" uniqKey="Lemke K" first="Krzysztof" last="Lemke">Krzysztof Lemke</name></noRegion><name sortKey="Baginski, Maciej" sort="Baginski, Maciej" uniqKey="Baginski M" first="Maciej" last="Baginski">Maciej Baginski</name><name sortKey="Skladanowski, Andrzej" sort="Skladanowski, Andrzej" uniqKey="Skladanowski A" first="Andrzej" last="Skladanowski">Andrzej Skladanowski</name><name sortKey="Skladanowski, Andrzej" sort="Skladanowski, Andrzej" uniqKey="Skladanowski A" first="Andrzej" last="Skladanowski">Andrzej Skladanowski</name><name sortKey="Wojciechowski, Marcin" sort="Wojciechowski, Marcin" uniqKey="Wojciechowski M" first="Marcin" last="Wojciechowski">Marcin Wojciechowski</name></country><country name="France"><region name="Île-de-France"><name sortKey="Lemke, Krzysztof" sort="Lemke, Krzysztof" uniqKey="Lemke K" first="Krzysztof" last="Lemke">Krzysztof Lemke</name></region><name sortKey="Bailly, Christian" sort="Bailly, Christian" uniqKey="Bailly C" first="Christian" last="Bailly">Christian Bailly</name><name sortKey="Laine, William" sort="Laine, William" uniqKey="Laine W" first="William" last="Laine">William Laine</name><name sortKey="Larsen, Annette K" sort="Larsen, Annette K" uniqKey="Larsen A" first="Annette K." last="Larsen">Annette K. Larsen</name></country><country name="Belgique"><noRegion><name sortKey="Colson, Pierre" sort="Colson, Pierre" uniqKey="Colson P" first="Pierre" last="Colson">Pierre Colson</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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