INTERACTION WITH DNA OF PHOTOACTIVE VIOLOGENS BASED ON THE 6-(2-PYRIDINIUM)PHENANTHRIDINIUM STRUCTURE

A new type of DNA-interacting viologens derived from the N,N'-dialkyl 6-(2-pyridinium)-phenanthridinium structure (in which dialkyl is -CH2 CH2-, -CH2 CH2 CH2-, or (-CH3)(2)) have been synthesized. Electronic s pectroscopy, steady-state and time-resolved fluorescence, cyclic volta mmetry, binding isotherms, viscosity titrations, and molecular modelin g techniques were employed to characterize the structural, photophysic al and redox properties of the novel drugs as well as the correspondin g drug-DNA complexes. The viologens display significant visible absorp tion(up to ca. 490 nn), and a rather intense luminescence (Phi(em) fro m 0.06 to 0.20 at 491-565 nm wavelength maxima) which is efficiently q uenched by DNA. The calculated redox potentials of these drugs in thei r singlet excited state (+ 2.1 V vs. SHE) predict a large driving forc e for a photoelectron transfer reaction from the nucleobases to the dr ugs. Photochemical measurements of the viologens in the presence of mo nonucleotides, nucleosides, and deoxyribose indicate that the observed fluorescence quenching occurs indeed by electron transfer from the DN A bases rather than the sugar phosphate backbone. Large association co nstants to double helical DNA (in the order of 10(5) M(-1)) have been evaluated from the absorbance-based binding isotherms. Viscosimetry su pports intercalation of the drugs into the DNA helix. Computer simulat ions (molecular mechanics of d(CGCGCG)(2)-drug complexes) confirm the intercalative nature of the binding and provide finer details about th e geometry of the different viologen-DNA complexes. Molecular modeling has also revealed a stereoselective interaction of the enantiomeric d rug conformers with the chiral DNA helix. A DNA-targeted drug design o f future generations of these ligands in order to improve and/or modul ate their photochemical, redox, and nucleic acid binding properties ap pears to be possible by a careful selection of the N,N'-dialkylating c hain and/or the substituents on the azaheterocyclic moieties.