title: Design of a composite ethidium-netropsin-anilinoacridine molecule for DNA recognition.
abstract: Control of gene expression is a cherished goal of cancer chemotherapy. Small ligand molecules able to bind tightly to DNA in a well-defined configuration are being actively searched for. With this goal in mind, we have designed and synthesized the trifunctional molecule R-132, which combines a bispyrrole skeleton for minor groove DNA recognition and two different chromophores, anilinoacridine and ethidium. The affinity and mode of binding of R-132 to DNA were studied by a combination of complementary biochemical and biophysical techniques, which included absorption and fluorescence spectroscopy and circular and linear dichroism. A surface plasmon resonance biosensor analysis was also performed to quantify the kinetic parameters of the drug-DNA interaction process. Altogether, the results demonstrate that the three moieties of the hybrid molecule are engaged in the interaction process, thus validating the rational design strategy. At the biological level, R-132 stabilizes topoisomerase-II-DNA covalent complexes and displays potent cytotoxic activities, which are attributable to its DNA-binding properties. R-132 easily enters and accumulates in cell nuclei, as evidenced by confocal microscopy. R-132 therefore provides a novel lead compound for the design of gene-targeted anticancer agents.
authors.affiliation: INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France.
authors.forename: Carolina
authors.initials: C
authors.lastname: Carrasco
authors.forename: Philippe
authors.initials: P
authors.lastname: Helissey
authors.forename: Michelyne
authors.initials: M
authors.lastname: Haroun
authors.forename: Brigitte
authors.initials: B
authors.lastname: Baldeyrou
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Pierre
authors.initials: P
authors.lastname: Colson
authors.forename: Claude
authors.initials: C
authors.lastname: Houssier
authors.forename: Sylviane
authors.initials: S
authors.lastname: Giorgi-Renault
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D018983:DNA Footprinting; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D015195:Drug Design; D004996:Ethidium / Q000737:chemistry* / Q000494:pharmacology; D018390:Gene Targeting; D007202:Indicators and Reagents; D007700:Kinetics; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D018613:Microscopy, Confocal; D009429:Netropsin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D013055:Spectrophotometry, Infrared; D020349:Surface Plasmon Resonance
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009429:Netropsin; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004996:Ethidium