title: Relationship between the structure and the DNA binding properties of diazoniapolycyclic duplex- and triplex-DNA binders: efficiency, selectivity, and binding mode.
abstract: The association of dicationic polycyclic ligands, namely, four diazoniapentaphene derivatives, three diazoniaanthra[1,2-a]anthracenes, diazoniahexaphene, and a partly saturated hydroxy-substituted diazoniapentaphene with double-stranded and triple-helical DNA, was investigated by spectrophotometric and viscosimetric titrations, CD and LD spectroscopy, DNA melting experiments, and molecular modeling studies. All experimental and theoretical data reveal an intercalative DNA-binding mode of the diazoniapentaphenes and diazoniaanthra[1,2-a]anthracenes; the latter have approximately 10-fold higher affinity for the DNA duplex. CD spectroscopic investigations and molecular modeling studies show that only one azonianaphthalene part of the ligand is intercalated between the DNA base pairs, whereas the remaining part of the ligand points outside the intercalation pocket. In contrast, the diazoniahexaphene is a DNA groove binder, which binds selectively to [poly(dAdT)]2. At low ligand-to-DNA ratios (r < 0.15), the diazoniahexaphene also behaves as an intercalator; however, all spectroscopic and viscosimetric data are consistent with significant groove binding of this ligand at r > 0.2. Studies of the interaction of diazoniapolycyclic ions with triplex DNA reveal a preferential binding of both diazoniapentaphenes and diazoniaanthra[1,2-a]anthracenes to the triplex and stabilization thereof. These properties are more pronounced in the case of the hexacyclic diazoniaanthra[1,2-a]anthracenes; however, the diazoniahexaphene shows no preferential binding to the triplex. The DNA binding properties of the diazoniapentaphene derivatives remain essentially the same upon variation of the positions of nitrogen atoms or substitution with methyl groups. In contrast, the interactions of the diazoniaanthra[1,2-a]anthracence isomers with triplex DNA are slightly different. Notably, the 14a,16a-diazoniaanthra[1,2-a]anthracene is among the most efficient triplex stabilizers, with a 9-fold larger binding affinity for the triplex than for the DNA duplex. Moreover, the diazoniapentaphene and diazoniaanthra[1,2-a]anthracene derivatives represent the first examples of triplex-DNA binders that do not require additional aminoalkyl side chains for efficient triplex stabilization.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, via Marzolo 5, I-35131 Padova, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Basili
authors.forename: Anna
authors.initials: A
authors.lastname: Bergen
authors.forename: Francesco
authors.initials: F
authors.lastname: Dall'Acqua
authors.forename: Anita
authors.initials: A
authors.lastname: Faccio
authors.forename: Anton
authors.initials: A
authors.lastname: Granzhan
authors.forename: Heiko
authors.initials: H
authors.lastname: Ihmels
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000179:Acrylates / Q000493:pharmacokinetics; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D003979:Diazonium Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000493:pharmacokinetics; D008954:Models, Biological; D008958:Models, Molecular; D011083:Polycyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014783:Viscosity
chemical_list: D000179:Acrylates; D003979:Diazonium Compounds; D006576:Heterocyclic Compounds, 4 or More Rings; D011083:Polycyclic Compounds; C051802:triplex DNA; D004247:DNA; C427203:calf thymus DNA; C041756:alpha,beta-diacryloxypropionic acid