Tight binding of the antitumor drug ditercalinium to quadruplex DNA.
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 complexes with triplex and quadruplex structures. The preferential interaction of the drug with four-stranded DNA structures was independently confirmed by electrospray mass spectrometry and a detailed analysis of the binding reaction was performed by surface plasmon resonance (SPR) spectroscopy. 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 perspectives for the design of drugs that can bind to human telomeres.
Carrasco
Carolina
C
INSERM U-524 et Laboratoire de Pharmacologie, Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France.
Rosu
Frédéric
F
Gabelica
Valérie
V
Houssier
Claude
C
De Pauw
Edwin
E
Garbay-Jaureguiberry
Christiane
C
Roques
Bernard
B
Wilson
W David
WD
Chaires
Jonathan B
JB
Waring
Michael J
MJ
Bailly
Christian
C
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001667:Binding, Competitive; D002227:Carbazoles / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D054856:G-Quadruplexes; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D016615:Telomere / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D002227:Carbazoles; D007364:Intercalating Agents; D004247:DNA; C042804:ditercalinium