Kaiser, Markus; Sainlos, Matthieu; Lehn, Jean-Marie; Bombard, Sophie; Teulade-Fichou, Marie-Paule:

Aminoglycoside-quinacridine conjugates: Towards recognition of the P6.1 element of Telomerase RNA.

In: ChemBioChem : a European journal of chemical biology, Jg. 7 (2006) ; Nr. 2, S. 321-329
ISSN: 1439-4227
Zeitschriftenaufsatz / Fach: Biologie
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.