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Linkage of a Triple Helix-Forming Oligonucleotide to Amsacrine-4-carboxamide Derivatives Modulates the Sequence-Selectivity of Topoisomerase II-Mediated DNA Cleavage |
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| Authors: | Paola Arimondo Christian Bailly Alexandre Boutorine Ulysse Asseline Jian-Sheng Sun ThÉRÈSe Garestier |
| Institution: | 1. Laboratoire de Biophysique, UMR 8646 CNRS-Muséum National d'Histoire Naturelle, INSERM U201 , 43 rue Cuvier, 75005, Paris, France;2. INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL , Place de Verdun, 59045, Lille cedex, France;3. INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL , Place de Verdun, 59045, Lille cedex, France;4. Laboratoire de Biophysique, UMR 8646 CNRS-Muséum National d'Histoire Naturelle, INSERM U201 , 43 rue Cuvier, 75005, Paris, France;5. Centre de Biophysique Moléculaire, CNRS UPR 4301 , Rue Charles-Sadron, 45071, Orléans cedex 2, France |
| Abstract: | Abstract Amsacrine-4-carboxamide-oligonucleotide conjugates were synthesized and studied for their capacity to form DNA triple helices and to alter human topoisomerase II binding and cleavage properties. The intercalating agent was attached to the 3′- or the 5′-end of a 24 nt triple helix-forming oligonucleotide via linkers of different lengths. The stability of these DNA triple helices was investigated by gel retardation and melting temperature studies using a synthetic 70 bp DNA duplex target. The effect of the conjugates on DNA cleavage by topoisomerase II was evaluated using the 70 bp duplex and a 311 bp restriction fragment containing the same triple helix site. The conjugate with the amsacrine derivative linked to the 3′ end of the TFO via a hexaethylene glycol linker modulates the extent of DNA cleavage by topoisomerase II at specific sites. |
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