Kaya Kemal, Johnson Madeleine, Alabugin Igor V
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL.
Photochem Photobiol. 2015 May-Jun;91(3):748-58. doi: 10.1111/php.12412. Epub 2015 Jan 29.
Photochemical activation of meta-diynes incapable of Bergman and C1-C5 cyclizations still leads to efficient double-strand DNA cleavage. Spatial proximity of the two arylethynyl groups is not required for efficient DNA photocleavage by the enediyne-lysine conjugates. Efficiency of the cleavage is a function of the external pH and DNA damage is strongly enhanced at pH < 7. The pH-dependence of the DNA photocleavage activity stems from the protonation states of lysine amino groups, the internal electron donors responsible for intramolecular PET quenching and deactivation of the photoreactive excited states. DNA-binding analysis suggests intercalative DNA binding for phenyl substituted conjugate and groove binding for TFP-substituted conjugate. Additional insights in the possible mechanism for DNA damage from the ROS (Reactive Oxygen Species) scavenger experiments found that generation of singlet oxygen is partially involved in the DNA damage.
无法进行伯格曼环化和C1-C5环化的间二炔的光化学活化仍能高效地切割双链DNA。对于烯二炔-赖氨酸共轭物高效光切割DNA而言，两个芳基乙炔基的空间接近并非必需。切割效率是外部pH值的函数，在pH < 7时DNA损伤会显著增强。DNA光切割活性的pH依赖性源于赖氨酸氨基的质子化状态，赖氨酸氨基是负责分子内PET猝灭和光反应性激发态失活的内部电子供体。DNA结合分析表明，苯基取代的共轭物以插入方式结合DNA，而TFP取代的共轭物以沟槽方式结合DNA。通过活性氧（ROS）清除剂实验对DNA损伤可能机制的进一步研究发现，单线态氧的产生部分参与了DNA损伤。
