Directing Quadruplex-Stabilizing Drugs to the Telomere: Synthesis and Properties of Acridine−Oligonucleotide Conjugates
- Joan Casals
- ,
- Laurent Debéthune
- ,
- Karine Alvarez
- ,
- Antonina Risitano
- ,
- Keith R. Fox
- ,
- Anna Grandas
- , and
- Enrique Pedroso
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Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain, and School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K
Abstract
Conjugates containing quadruplex-stabilizing acridines linked to oligonucleotides that are complementary to the G-rich human telomere sequence were synthesized. Acylation of 3,6-diaminoacridine followed by two Michael reactions provided derivatives suitable for conjugation, which were coupled to resin-linked amine-modified oligonucleotides by activating the carboxyl group with pentafluorophenyl 4-nitrobenzenesulfonate. After deprotection with aqueous ammonia at room temperature, conjugates incorporating different acridines, linkers, and oligonucleotide sequences were obtained. These were tested for their ability to stabilize intramolecular DNA quadruplexes that are based on the human telomeric repeat sequence (GGGTTA)n.
†
Universitat de Barcelona.
‡
University of Southampton.
*
Corresponding authors. (E.P.) Email: [email protected]. Phone: + 34 93 403 4824. (K.R.F.) Email [email protected]. Phone: +44 (0)23 8059 4374. Fax: +44 (0)23 8059 4459.
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