Search for DNA repair inhibitors: selective binding of nucleic bases-acridine conjugates to a DNA duplex containing an abasic site.
The abasic site is one of the most frequent DNA lesions generated by spontaneous or enzymatic cleavage of the N-glycosidic bond. The abasic site is also an intermediate in the nucleotide and base excision DNA repair. We examined molecules which recognize and cleave DNA at the abasic site with high efficiency. These molecules incorporate in their structure a nucleic base for abasic site recognition, an intercalator for DNA binding, and a polyamino linker for ionic interaction and DNA cleavage. Such compounds, by interfering with abasic sites in DNA, are also inhibitors of DNA repair. In order to better understand the parameters of the interaction, we carried out a UV thermal denaturation study of synthetic oligonucleotides containing the lesion both in the absence and in the presence of the drugs. A similar study was also carried out using the corresponding nonmodified oligonucleotide. The results indicate selective binding of the base-chain-intercalator conjugates to the abasic site containing oligonucleotides.
Berthet
N
N
L.E.D.S.S., Chimie Bioorganique, UMR CNRS 5616, Université Joseph Fourier, Grenoble, France.
Constant
J F
JF
Demeunynck
M
M
Michon
P
P
Lhomme
J
J
D000166:Acridines / Q000378:metabolism* / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D006358:Hot Temperature; D007364:Intercalating Agents / Q000378:metabolism* / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology; D013053:Spectrophotometry; D013816:Thermodynamics; D017186:Titrimetry; D014466:Ultraviolet Rays
D000166:Acridines; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D012965:Sodium Chloride