title: Bis-phenanthroline derivatives as suitable scaffolds for effective G-quadruplex recognition.
abstract: Selective recognition of DNA folding is central to multiple biological and pharmacological applications aimed at precise targeting of distinct genomic regions. Here, we focused on the recognition of physiologically relevant G-quadruplex (G-4) structures by bis-phenanthroline (bis-Phen) ligands containing two Phen moieties covalently linked through an amine or thioether bond. The transition metal ions Mn(2+), Ni(2+), Cu(2+), and the biologically relevant Mg(2+) and Zn(2+) efficiently form 1 : 1 bis-Phen complexes characterised by a large planar structure fit to successfully recognise G-quartet arrangements.Interestingly, metal ion complexation dramatically affects ligand-stabilising effects on G-quadruplex, the melting temperature of the folded structure being increased up to 30 degrees C at ligand concentrations as low as 1 microM in the presence of Ni(2+) and Cu(2+). In addition, the test complexes were able to induce G-4 formation from essentially unfolded G-rich sequences even in the absence of K(+) ions as shown by gel shift and circular dichroism experiments. In line with their G-4 stabilising properties bis-Phen complexes are effective inhibitors of telomerase activity, Ni(II) complexes being effective in the sub-micromolar range. This is combined with lack of unselective DNA-damaging activity and short-term cellular toxicity, which makes the novel compounds (above all their Ni(II) complexes) interesting antiproliferative drug leads.
authors.affiliation: Dept. of Pharmaceutical Sciences, v. Marzolo 5, 35131, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bianco
authors.forename: C
authors.initials: C
authors.lastname: Musetti
authors.forename: A
authors.initials: A
authors.lastname: Waldeck
authors.forename: S
authors.initials: S
authors.lastname: Sparapani
authors.forename: J D
authors.initials: JD
authors.lastname: Seitz
authors.forename: A P
authors.initials: AP
authors.lastname: Krapcho
authors.forename: M
authors.initials: M
authors.lastname: Palumbo
authors.forename: C
authors.initials: C
authors.lastname: Sissi
mesh_terms: D002942:Circular Dichroism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D053837:DNA Cleavage / Q000187:drug effects; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D008670:Metals / Q000737:chemistry; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D008670:Metals; D009942:Organometallic Compounds; D010618:Phenanthrolines; D004247:DNA; D019098:Telomerase