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Nucleic Acids Research 2005 33(18):6034-6047; doi:10.1093/nar/gki904
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Published online 27 October 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

Induction of unique structural changes in guanine-rich DNA regions by the triazoloacridone C-1305, a topoisomerase II inhibitor with antitumor activities

Krzysztof Lemke1,4, Marcin Wojciechowski1, William Laine2, Christian Bailly2, Pierre Colson3, Maciej Baginski1, Annette K. Larsen4 and Andrzej Skladanowski1,*

1Laboratory of Cellular and Molecular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology Gdansk, Poland 2INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL 59045 Lille Cedex, France 3Biospectroscopy and Physical Chemistry Unit, Department of Chemistry and Natural and Synthetic Drugs Research Center, University of Liège Sart-Tilman, 4000, Liège, Belgium 4Group of Biology and Pharmacogenetics of Human Tumors, INSERM U673, Université Pierre et Marie Curie (UPMC-Paris 6), Hôpital Saint-Antoine Paris, 75571 Paris 12, France

*To whom correspondence should be addressed. Tel: +48 58 3471749; Fax: +48 58 3471144; Email: as{at}altis.chem.pg.gda.pl

Received September 8, 2005. Revised September 29, 2005. Accepted September 29, 2005.

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.

Present address: Christian Bailly, Centre de Recherche en Oncologie Expérimentale, Institut de Recherche Pierre Fabre, 3 rue des satellites, 31140 Toulouse, France


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