Volume 7, Issue 2 p. 321-329
Full Paper

Aminoglycoside–Quinacridine Conjugates: Towards Recognition of the P6.1 Element of Telomerase RNA

Markus Kaiser Dr.

Markus Kaiser Dr.

Laboratoire de Chimie des Interactions Moléculaires, CNRS UPR 285, Collège de France, 11 place Marcelin Berthelot, 75251 Paris Cedex 05, France, Fax: (+33) 144-271-356

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Matthieu Sainlos Dr.

Matthieu Sainlos Dr.

Laboratoire de Chimie des Interactions Moléculaires, CNRS UPR 285, Collège de France, 11 place Marcelin Berthelot, 75251 Paris Cedex 05, France, Fax: (+33) 144-271-356

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Jean-Marie Lehn Prof.

Jean-Marie Lehn Prof.

Laboratoire de Chimie des Interactions Moléculaires, CNRS UPR 285, Collège de France, 11 place Marcelin Berthelot, 75251 Paris Cedex 05, France, Fax: (+33) 144-271-356

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Sophie Bombard Dr.

Sophie Bombard Dr.

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Université Paris V, 45 rue des St Pères, 75270 Paris Cedex 06, France

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Marie-Paule Teulade-Fichou Dr.

Marie-Paule Teulade-Fichou Dr.

Laboratoire de Chimie des Interactions Moléculaires, CNRS UPR 285, Collège de France, 11 place Marcelin Berthelot, 75251 Paris Cedex 05, France, Fax: (+33) 144-271-356

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First published: 30 January 2006
Citations: 19

Graphical Abstract

Embracing RNA hairpins: A rapid and modular strategy was developed to construct a series of monomeric and dimeric aminoglycoside–quinacridine conjugates. A dimeric conjugate derived from tobramycin showed remarkable binding selectivity for the P6.1 element of telomerase RNA, which suggested a double wrapping around the stem-loop structure (see schematic representation). A molecular scaffold for small-sized RNA-hairpin recognition, usable for the inhibition of telomerase, was identified.

Abstract

A modular synthesis has been developed which allows easy and rapid attachment of one or two aminoglycoside units to a quinacridine intercalator, thereby leading to monomeric and dimeric conjugates. Melting temperature (Tm) experiments show that the tobramycin dimeric conjugate TD1 exhibits strong binding to the P6.1 element of human telomerase RNA. By contrast, tobramycin alone is much less efficient and the monomeric compound TM1 elicits a poor binding ability. Monitoring of the interaction by an electrophoretic mobility shift assay shows a 1:1 stoichiometry for the binding of the dimeric compound to the hairpin structure and confirms the lower affinity for a control duplex. Protection experiments with RNase T1 indicate interaction of the drug both in the stem and in the loop of the hairpin. Taken together, the data suggest a binding of TD1 inside the hairpin at the stem-loop junction. The same trends are observed with paromomycin and kanamycin analogues but with a lower affinity.