UMR9187 / U1196 – Chimie et Modélisation pour la Biologie du Cancer (CMBC)

Publications de l’unité

Année de publication : 1999

M Jourdan, J Garcia, J Lhomme, M P Teulade-Fichou, J P Vigneron, J M Lehn (1999 Nov 26)

Threading bis-intercalation of a macrocyclic bisacridine at abasic sites in DNA: nuclear magnetic resonance and molecular modeling study.

Biochemistry : 38 : 14205-14213 : DOI : 10.1021/bi991111h En savoir plus
Résumé

The macrocyclic bisacridine (CBA) has been reported previously to specifically recognize single-stranded nucleic acid structures, especially DNA hairpins. The binding of the drug with an abasic site-containing oligonucleotide, was investigated by 1H NMR and molecular modeling. We have used a DNA undecamer, the d(C1G2C3A4C5X6C7A8C9G10C11)·d(G12C13G14T15G16T17G18T19G20C21G22) duplex in which the X residue is a stable analogue of the abasic site [3-hydroxy-2-(hydroxymethyl) tetrahydrofuran]. Analysis of the NMR data reveals that the bisacridine molecule forms two different intercalation complexes in a 80/20 (± 10) ratio. For the major complex, a molecular modeling study was performed guided by nineteen intermolecular drug−DNA restraints, determined from NOESY spectra. In this model, the ligand interacts in the threading binding mode with an acridine ring intercalated between the C7−A8 and T15−G16 base pairs, while the other acridine ring resides in the abasic pocket. The two linker chains are positioned in the minor and in the major groove, respectively. A comparable study was performed to evaluate the interaction of CBA with the parent unmodified duplex in which X6 was replaced by an adenine residue. No complex formation was observed when operating in identical conditions. This shows the selective binding of CBA to the abasic site and its potential interest to target the abasic site lesion.

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Année de publication : 1998

A J Blacker, M P Teulade-Fichou, J P Vigneron, M Fauquet, J M Lehn (1998 Mar 17)

Selective photocleavage of single-stranded nucleic acids by cyclobisintercaland molecules.

Bioorganic & medicinal chemistry letters : 8 : 601-606 : DOI : 10.1016/s0960-894x(98)00085-7 En savoir plus
Résumé

Irradiation of mixtures of a single-stranded circular plasmid and of a double-stranded supercoiled DNA in presence of the cyclobisintercaland compounds 2 or 3 shows that these reagents effect the selective photocleavage of the single-stranded entity. Furthermore, 2 also cleaves tRNAasp preferentially at single-stranded domains.

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Année de publication : 1997

A Slama-Schwok, F Peronnet, E Hantz-Brachet, E Taillandier, M P Teulade-Fichou, J P Vigneron, M Best-Belpomme, J M Lehn (1997 Jul 1)

A macrocyclic bis-acridine shifts the equilibrium from duplexes towards DNA hairpins.

Nucleic acids research : 25 : 2574-2581 : DOI : 10.1093/nar/25.13.2574 En savoir plus
Résumé

Nucleic acids can undergo dynamic conformational changes associated with the regulation of biological processes. A molecule presenting larger affinities for alternative structures relative to a duplex is expected to modify such conformational equilibria. We have previously reported that macrocyclic bis-acridine binds preferentially to single-stranded regions, especially DNA hairpins, due to steric effects. Here, we show, using gel electrophoresis, fluorescence and melting temperature experiments, that the macrocycle bis-acridine shifts an equilibrium from a duplex towards the corresponding hairpins. Competition experiments enlighten the higher affinity of the macrocycle for hairpins compared with double-stranded DNA. The macrocycle bis-acridine destabilizes a synthetic polynucleotide, by the formation of premelted areas. By extrapolation, the macrocycle bis-acridine should be able to disrupt, at least locally, genomic DNA duplexes and to stabilize unpaired areas, especially palindromic ones forming hairpins. Such macrocyclic compounds may have potential applications in the therapy of diseases involving hairpins.

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