Multiple Binding Modes of the Camptothecin Family to DNA Oligomers

The binding constants of camptothecin, topotecan and its lactone ring‐opened carboxylate derivative to DNA octamers were measured by UV and NMR spectroscopy. The self‐association of topotecan (TPT) was also measured. The carboxylate form of TPT binds in the same way as the lactone, but more weakly....

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Bibliographic Details
Published in:Chemistry : a European journal 2004-11, Vol.10 (22), p.5776-5787
Main Authors: Bocian, Wojciech, Kawȩcki, Robert, Bednarek, Elzbieta, Sitkowski, Jerzy, Pietrzyk, Agnieszka, Williamson, Michael P., Hansen, Poul Erik, Kozerski, Lech
Format: Article
Language:English
Subjects:
alkaloids
antitumor agents
Camptothecin - chemistry
Camptothecin - classification
conformation analysis
DNA - chemistry
docking
Hydrogen-Ion Concentration
Hydrolysis
Lactones - chemistry
Magnetic Resonance Spectroscopy
Models, Biological
Molecular Structure
NMR spectroscopy
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Summary:The binding constants of camptothecin, topotecan and its lactone ring‐opened carboxylate derivative to DNA octamers were measured by UV and NMR spectroscopy. The self‐association of topotecan (TPT) was also measured. The carboxylate form of TPT binds in the same way as the lactone, but more weakly. Titration of TPT into d(GCGATCGC)2 shows a preferred location stacked onto the terminal G1 base. However, the intermolecular NOEs cannot be reconciled with a single conformation of the complex, and suggest a model of a limited number of conformations in fast exchange. MD calculations on four pairs of starting structures with TPT stacked onto the G1–C8 base pair in different orientations were therefore performed. The use of selected experimental “docking” restraints yielded ten MD trajectories covering a wide conformational space. From a combination of calculated free energies, NOEs and chemical shifts, some of the structures produced could be eliminated, and it is concluded that the data are consistent with two major families of conformations in fast exchange. One of these is the conformation found in a crystal of a TPT/DNA/topoisomerase I ternary complex [Proc. Natl. Acad. Sci. USA 2002, 99, 15 387–15 392]. A novel combination of experimental and theoretical methods dealing with the conformational ensemble of drug/biomolecule complexes exemplified by topotecan (TPT)/DNA interaction is presented (see scheme).
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.200305624