Interaction between double helix DNA fragments and a new topopyrone acting as human topoisomerase I poison.
A water soluble derivative (2) of topopyrones was selected for NMR studies directed to elucidate the mode of binding with specific oligonucleotides. Topopyrone 2 can intercalate into the CG base pairs, but the residence time into the double helix is very short and a fast chemical exchange averaging occurs at room temperature between the free and bound species. The equilibria involved become slow below room temperature, thus allowing to measure a mean lifetime of the complex of ca. 7 ms at 15 degrees C. Structural models of the complex with d(CGTACG)(2) were developed on the basis of DOSY, 2D NOESY and (31)P NMR experiments. Topopyrone 2 presents a strong tendency to self-associate. In the presence of oligonucleotide a certain number of ligand molecules are found to externally stack to the double-helix, in addition to a small fraction of the same ligand intercalated. The external binding to the ionic surface of the phosphoribose chains may thus represents the first step of the intercalation process.
Scaglioni
Leonardo
L
Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, via Celoria 2, 20133 Milano, Italy.
Mazzini
Stefania
S
Mondelli
Rosanna
R
Dallavalle
Sabrina
S
Gattinoni
Sonia
S
Tinelli
Stella
S
Beretta
Giovanni L
GL
Zunino
Franco
F
Ragg
Enzio
E
D000880:Anthraquinones / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents; D009682:Magnetic Resonance Spectroscopy; D009690:Nucleic Acid Conformation; D011753:Pyrones / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D059004:Topoisomerase I Inhibitors
D000880:Anthraquinones; D007364:Intercalating Agents; D011753:Pyrones; D059004:Topoisomerase I Inhibitors; D004247:DNA