Induction of unique structural changes in guanine-rich DNA regions by the triazoloacridone C-1305, a topoisomerase II inhibitor with antitumor activities.
We recently reported that the antitumor triazoloacridone, compound C-1305, is a topoisomerase II poison with unusual properties. In this study we characterize the DNA interactions of C-1305 in vitro, in comparison with other topoisomerase II inhibitors. Our results show that C-1305 binds to DNA by intercalation and possesses higher affinity for GC- than AT-DNA as revealed by surface plasmon resonance studies. Chemical probing with DEPC indicated that C-1305 induces structural perturbations in DNA regions with three adjacent guanine residues. Importantly, this effect was highly specific for C-1305 since none of the other 22 DNA interacting drugs tested was able to induce similar structural changes in DNA. Compound C-1305 induced stronger structural changes in guanine triplets at higher pH which suggested that protonation/deprotonation of the drug is important for this drug-specific effect. Molecular modeling analysis predicts that the zwitterionic form of C-1305 intercalates within the guanine triplet, resulting in widening of both DNA grooves and aligning of the triazole ring with the N7 atoms of guanines. Our results show that C-1305 binds to DNA and induces very specific and unusual structural changes in guanine triplets which likely plays an important role in the cytotoxic and antitumor activity of this unique compound.
Lemke
Krzysztof
K
Laboratory of Cellular and Molecular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Gdansk, Poland.
Wojciechowski
Marcin
M
Laine
William
W
Bailly
Christian
C
Colson
Pierre
P
Baginski
Maciej
M
Larsen
Annette K
AK
Skladanowski
Andrzej
A
D000166:Acridines / Q000737:chemistry* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D018983:DNA Footprinting; D003850:Deoxyribonuclease I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity; D006147:Guanine / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry* / Q000633:toxicity; D008958:Models, Molecular; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014230:Triazoles / Q000737:chemistry* / Q000633:toxicity
D000166:Acridines; D000970:Antineoplastic Agents; C488734:C 1305; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; C437127:O,O-diethylphosphorylcholine iodide; D059005:Topoisomerase II Inhibitors; D014230:Triazoles; D010767:Phosphorylcholine; D006147:Guanine; D004247:DNA; D003850:Deoxyribonuclease I