Tight binding of the antitumor drug ditercalinium to quadruplex DNA
English
Carrasco, Carolina[INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, Lille, France > > > >]
Rosu, Frédéric[Université de Liège - ULg > > Chimie physique, spectrométrie de masse >]
Gabelica, Valérie[Université de Liège - ULg > > Chimie physique, spectrométrie de masse >]
Houssier, Claude[Université de Liège - ULg > > Chimie Macromoléculaire et Chimie Physique >]
De Pauw, Edwin[Université de Liège - ULg > > Chimie physique, spectrométrie de masse >]
Garbay-Jaureguiberry, Christiane[Département de Pharmacochimie Moléculaire et Structurale INSERM U266 CNRS UMR 8600 Faculte de Pharmacie, 4 Avenue de l'Observatoire 75270 Paris (France) > > > >]
Roques, Bernard[Département de Pharmacochimie Moléculaire et Structurale INSERM U266 CNRS UMR 8600 Faculte de Pharmacie, 4 Avenue de l'Observatoire 75270 Paris (France) > > > >]
Wilson, W David[Department of Chemistry Georgia State University, Atlanta, GA 30303 (USA) > > > >]
Chaires, Jonathan B[Department of Biochemistry University of Mississippi Medical Center 2500 N.State St., Jackson, MS 9216-4505 (USA) > > > >]
Waring, Michael J[Department of Pharmacology University of Cambridge, Tennis Court Road Cambridge CB2 1QJ (UK) > > > >]
Bailly, Christian[INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, Lille, France > > >]
[en] antitumor agents ; DNA ; equilibrium dialysis ; mass spectrometry ; surface plasmon resonance ; noncovalent
[en] The structural selectivity of the DNA-binding antitumor drug ditercalinium was investigated by competition dialysis with a series of nineteen different DNA substrates. The 7H-pyridocarbazole dimer was found to bind to double stranded DNA with a preference for GC rich species but can in addition form stable complex with triplex and quadruplex structures. The preferential interaction of the drug with four-stranded DNA structures was independantly confirmed by electrospray mass spectrometry and a detailed analysis of the binding reaction was performed by surface plasmon resonance (SPR) spectrospray. The BIAcore SPR study showed that the kinetic parameters for the interaction of ditercalinium with the human telomeric quadruplex sequence are comparable to those measured with a duplex sequence. Slow association and dissociation were observed with both the quadruplex and duplex structures. The newly discovered preferential binding of ditercalinium to the antiparallel quadruplex sequence d(AG(3)[T(2)AG(3)](3)) provides new perspective for the design of drugs that can bind to human telomeres.
Centre Interfacultaire d'Analyse des Résidus en Traces - CART
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS