Interaction of an acridine dimer with DNA quadruplex structures.
The reactivation of telomerase activity in most cancer cells supports the concept that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. The telomeric G-rich single-stranded DNA can adopt an intramolecular G-quadruplex structure in vitro, which has been shown to inhibit telomerase activity. The C-rich sequence can also adopt a quadruplex (intercalated) structure (i-DNA). Two acridine derivatives were shown to increase the melting temperature of the G- quadruplex and the C-quadruplex at 1 microM dye concentration. The increase in Tm value of the G-quadruplex was associated with telomerase inhibition in vitro. The most active compound, "BisA", showed an IC(50) value of 0.75 microM in a standard TRAP assay.
Alberti
P
P
Laboratoire de Biophysique, Muséum National d'Histoire Naturelle, INSERM U 201,CNRS UMR 8646, Paris, France.
Ren
J
J
Teulade-Fichou
M P
MP
Guittat
L
L
Riou
J F
JF
Chaires
J
J
Hélène
C
C
Vigneron
J P
JP
Lehn
J M
JM
Mergny
J L
JL
D000166:Acridines / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000378:metabolism*; D003596:Cytosine / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000737:chemistry; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000378:metabolism; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry; D012235:Rhodamines / Q000378:metabolism; D013050:Spectrometry, Fluorescence / Q000379:methods; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000737:chemistry; D013696:Temperature
D000166:Acridines; C451420:BisA compound; D001952:Bridged-Ring Compounds; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D008024:Ligands; C451421:MonoA compound; D009841:Oligonucleotides; D012235:Rhodamines; D006147:Guanine; D003596:Cytosine; D004247:DNA; D019098:Telomerase