Interaction with DNA of photoactive viologens based on the 6-(2- pyridinium)phenanthridinium structure.
A new type of DNA-interacting violgens derived from the N,N'-dialkyl 6-(2-pyridinium)-phenanthridinium structure (in which dialkyl is -CH2CH2-,-CH2CH2CH2-, or (-CH3)2) have been synthesized. Electronic spectroscopy, steady-state and time-resolved fluorescence, cyclic voltammetry, binding isotherms, viscosity titrations, and molecular modeling techniques were employed to characterize the structural, photophysical and redox properties of the novel drugs as well as the corresponding drug-DNA complexes. The viologens display significant visible absorption (up to ca. 490 nm), and a rather intense luminescence (phi cm from 0.06 to 0.20 at 491-565 nm wavelength maxima) which is efficiently quenched by DNA. The calculated redox potentials of these drugs in their singlet excited state (+2.1 V vs. SHE) predict a large driving force for a photoelectron transfer reaction from the nucleobases to the drugs. Photochemical measurements of the viologens in the presence of mononucleotides, nucleosides, and deoxyribose indicate that the observed fluorescence quenching occurs indeed by electron transfer from the DNA bases rather than the sugar phosphate backbone. Large association constants to double helical DNA (in the order of 10(5) M-1) have been evaluated from the absorbance-based binding isotherms. Viscosimetry supports intercalation of the drugs into the DNA helix. Computer simulations (molecular mechanics of d(CGCGCG)2-drug complexes) confirm the intercalative nature of the binding and provide finer details about the geometry of the different viologen-DNA complexes. Molecular modeling has also revealed a stereoselective interaction of the enantiomeric drug conformers with the chiral DNA helix. A DNA-targeted drug design of future generations of these ligands in order to improve and/or modulate their photochemical, redox, and nucleic acid binding properties appears to be possible by a careful selection of the N,N'-dialkylating chain and/or the substituents on the azaheterocyclic moieties.
Colmenarejo
G
G
Department of Biochemistry and Molecular Biology I, Faculty of Chemistry, Complutense University of Madrid, Spain.
Gutiérrez-Alonso
M C
MC
Bárcena
M
M
Kelly
J M
JM
Montero
F
F
Orellana
G
G
D001483:Base Sequence; D002412:Cations; D003196:Computer Graphics; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D004355:Drug Stability; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000737:chemistry; D010084:Oxidation-Reduction; D010617:Phenanthridines / Q000737:chemistry*; D010777:Photochemistry; D012996:Solutions; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D017186:Titrimetry; D014755:Viologens / Q000737:chemistry*; D014783:Viscosity
D002412:Cations; C094139:N,N'-dimethyl-6-(2-pyridinium)phenanthridinium; C094137:N,N'-ethylene-6-(2-pyridinium)phenanthridinium; C094138:N,N'-propylene-6-(2-pyridinium)phenanthridinium; D009711:Nucleotides; D010617:Phenanthridines; D012996:Solutions; D014755:Viologens; D004247:DNA