Colmenarejo G, Gutiérrez-Alonso M C, Bárcena M, Kelly J M, Montero F, Orellana G
Department of Biochemistry and Molecular Biology I, Faculty of Chemistry, Complutense University of Madrid, Spain.
J Biomol Struct Dyn. 1995 Feb;12(4):827-46. doi: 10.1080/07391102.1995.10508779.
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.
已合成了一种新型的与DNA相互作用的紫精，其衍生自N,N'-二烷基6-(2-吡啶基)-菲啶鎓结构（其中二烷基为-CH2CH2-、-CH2CH2CH2-或(-CH3)2）。采用电子光谱、稳态和时间分辨荧光、循环伏安法、结合等温线、粘度滴定以及分子建模技术来表征新型药物及其相应药物-DNA复合物的结构、光物理和氧化还原性质。这些紫精显示出显著的可见吸收（高达约490 nm）以及相当强的发光（在491 - 565 nm波长最大值处，荧光量子产率φcm为0.06至0.20），而这种发光会被DNA有效猝灭。这些药物在单重激发态下计算出的氧化还原电位（相对于标准氢电极，E0 = +2.1 V）预示着从核碱基到药物的光电子转移反应具有很大的驱动力。在单核苷酸、核苷和脱氧核糖存在下对紫精进行的光化学测量表明，观察到的荧光猝灭确实是通过从DNA碱基而非磷酸糖主链进行电子转移而发生的。基于吸光度的结合等温线评估出与双螺旋DNA的大缔合常数（约为10(5) M-1）。粘度测定法支持药物插入DNA螺旋。计算机模拟（d(CGCGCG)2 - 药物复合物的分子力学）证实了结合的插入性质，并提供了不同紫精 - DNA复合物几何结构的更详细信息。分子建模还揭示了对映体药物构象与手性DNA螺旋的立体选择性相互作用。通过仔细选择N,N'-二烷基化链和/或氮杂环部分上的取代基，似乎有可能对这些配体的下一代进行靶向DNA的药物设计，以改善和/或调节它们的光化学、氧化还原和核酸结合性质。
