Recognition of Abasic Sites in DNA by a Cyclobisacridine Molecule

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.

Abasic DNA structure, reactivity, and recognition

“…When illuminated in the presence of 32 P-labeled model abasic site containing duplex (23-mer), CBA induced selective photocleavage in the vicinity of the abasic lesion on both strands. 127 Combined high field nmr spectroscopy and restrained molecular dynamics calculations indicated formation of a major complex of the threading intercalation mode in which CBA penetrates the double helix at the abasic site sandwiching the base-pair 3Ј to the lesion between the two acridine rings, leaving the two protonated linking chains respectively in the major and in the minor groove (See Figure 13 on p. 78). 128 All these experiments suggest that the abasic lesion represents a site of strong thermodynamic destabilization in DNA and of enhanced flexibility.…”

Recognition of Single Stranded and Double Stranded DNA/RNA Sequences in Aqueous Medium by Small Bis-Aromatic Derivatives

“…Bis-acridine revealed also preference for binding to single stranded (ss) DNA in comparison with double stranded DNA [40]. Moreover, bis-acridine cleaved a 32 P-labeled duplex oligonucleotide containing one abasic site [43,44] and revealed selective photo-cleavage of singlestranded nucleic acids or single-stranded regions in complex nucleic acids like hairpins [45]. A structural explanation for the observed discrimination was that insertion into fully matched DNA is disfavoured because of steric hindrance due to the macrocyclic scaffold.…”

Macrocycles embedding phenothiazine or similar nitrogen and/or sulphur containing heterocycles

“…Quite a number of podands and macrocycles, as well as other derivatives, revealed applications as intercalating agents [65][66][67][68][69][70][71][72]. Macrocycles embedding these aromatic units also showed applications as sensors and chiral discriminators [73][74][75][76].…”

“…Cyclophanes 77a,b having two acridine units connected by aza or azaoxa bridges were obtained starting from 2,7-diformyl-acridine in reaction with diaminoethylether or with bis(aminoethyl)amine. 2,7-Diformyl-acridine was first transformed into macrocycles 84a,b with imine groups and then the reduction with NaBH 4 led to the target macrocycles 77a,b (yields for both processes 50-60 %; Scheme 27) [66,[69][70][71].…”

“…Macrocycles 77a,b revealed a high recognition ability for the abasic sites in DNA and Scheme 19 Synthesis of macrocycles with neomycine and acridine units Chart 7 Macrocycles with Nmethyl-acridone, acridane or acridinium units they produced the selective photocleavage in the vicinity of the abasic lesion. Macrocycle 83 proved to be more efficient as DNA-intercalator than the reference compounds 9-aminoacridine and spermine bisacridine [66,69,70,86,87]. Cyclophanes 77a,b and cryptand 78 were used in their oligoprotonated stages for detection of different anions (including several mono, di-and tri-carboxylates) by the modifications in the absorption and emission spectra upon the interaction between the macrocycles and the named anions [71,91].…”