No abstract

The ability of the cyclobisacridine CBA to recognize the abasic lesion in DNA was investigated with modified synthetic oligonucleotide duplexes. CBA was shown to cleave a 32 Plabeled duplex oligomer (23-mer) containing an apurinic site in the middle of the sequence. The interaction was examined with duplexes which contain a stable tetrahydrofuranyl analogue at the abasic site. Thermal denaturation experiments showed that CBA stabilizes an abasic undecamer duplex by a DT m value of 14 8C by forming a 1:1 complex, while no interaction was detected with the unmodified parent duplex. CBA displaced a nitroxide abasic site specific probe from the abasic duplex. When irradiated in the presence of a 32 Plabeled model abasic site containing duplex (23-mer), CBA induced selective photocleavage in the vicinity of the abasic lesion on both strands. All results demonstrate the high specificity of the interaction of CBA at the abasic lesion.

No abstract

The abasic site is a common lesion in DNA that is also formed as an intermediate in the base excision repair of damaged bases. We have previously reported the adenine-acridine conjugate 1 that was designed to bind to the abasic site and interfere with the repair process. High-field NMR had shown that 1 forms specific complexes with a DNA duplex containing an apurinic abasic site model. We report here the dynamics of the interaction of the nitroxide-labeled analogue 3 of the conjugate 1 with the same apurinic oligonucleotide and with the parent unmodified duplex. Identical study of the labeled acridine subunit 5 used as a reference is also reported. In the presence of the apurinic duplex and depending on the concentrations and drug ratios, three species are observed: the radical "free in solution", the "intercalation" complex characterized by its similarity to that observed in the presence of the parent unmodified duplex, and the "abasic-site-specific" complex which is the sole species visible at low drug ratios. The experimental data reinforced by molecular modeling of the complex and theoretical calculation of correlation times suggest (i) the most immobilized form corresponds to that observed by NMR and (ii) complexation of the drug is little or not modified by the spin-label. We also show that the abasic site constitutes a binding site for the propylaminoacridine intercalator 5.