Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA.
Beilstein J Org Chem. 2011;7:813-23. doi: 10.3762/bjoc.7.93. Epub 2011 Jun 16.
Hybrid molecules combining photoactivated aryl acetylenes and a dicationic lysine moiety cause the most efficient double-strand (ds) DNA cleavage known to date for a small molecule. In order to test the connection between the alkylating ability and the DNA-damaging properties of these compounds, we investigated the photoreactivity of three isomeric aryl-tetrafluoropyridinyl (TFP) alkynes with amide substituents in different positions (o-, m-, and p-) toward a model π-system. Reactions with 1,4-cyclohexadiene (1,4-CHD) were used to probe the alkylating properties of the triplet excited states in these three isomers whilst Stern-Volmer quenching experiments were used to investigate the kinetics of photoinduced electron transfer (PET). The three analogous isomeric lysine conjugates cleaved DNA with different efficiencies (34, 15, and 0% of ds DNA cleavage for p-, m-, and o-substituted lysine conjugates, respectively) consistent with the alkylating ability of the respective acetamides. The significant protecting effect of the hydroxyl radical and singlet oxygen scavengers to DNA cleavage was shown only with m-lysine conjugate. All three isomeric lysine conjugates inhibited human melanoma cell growth under photoactivation: The p-conjugate had the lowest CC(50) (50% cell cytotoxicity) value of 1.49 × 10(-7) M.
将光活化的芳基乙炔和二价赖氨酸部分结合在一起的混合分子导致了迄今为止小分子中二链 DNA 切割效率最高。为了测试这些化合物的烷基化能力和 DNA 损伤特性之间的联系，我们研究了三种具有酰胺取代基的不同位置（邻位、间位和对位）的芳基-四氟吡啶基（TFP）炔烃的光反应性与模型π-体系。用 1,4-环己二烯（1,4-CHD）反应来探测这三种异构体中三重态激发态的烷基化性质，而 Stern-Volmer 猝灭实验则用于研究光诱导电子转移（PET）的动力学。这三种类似的赖氨酸缀合物以不同的效率切割 DNA（对位、间位和邻位取代的赖氨酸缀合物的 ds DNA 切割率分别为 34%、15%和 0%），与相应的乙酰胺的烷基化能力一致。只有间位赖氨酸缀合物对 DNA 切割具有显著的羟基自由基和单线态氧清除剂的保护作用。三种异构体的赖氨酸缀合物在光激活下均抑制人黑色素瘤细胞生长：p-缀合物的 CC（50）（50%细胞毒性）值最低，为 1.49×10(-7)M。
