Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
Department of Pharmacology, Yale School of Medicine , New Haven, Connecticut 06520, United States.
J Am Chem Soc. 2016 Dec 7;138(48):15559-15562. doi: 10.1021/jacs.6b09657. Epub 2016 Nov 28.
(-)-Lomaiviticin A (1) is a C-symmetric cytotoxin that contains two diazofluorene functional groups and which induces double-strand breaks (DSBs) in DNA. Evidence suggests DNA cleavage is initiated by hydrogen atom abstraction from the deoxyribose backbone. Here we demonstrate the formation of the vinyl radicals 1· and 2· from 1 by 1,7-addition of thiols to the diazofluorenes. These radicals can affect hydrogen atom abstraction from methanol and acetone. The first addition of thiol to 1 proceeds at a much greater rate than the second. The diazosulfide 5 formed en route to 1· has been detected at -50 °C and undergoes decomposition to 1· with a half-life of 110 min at -20 °C under air. These data, which constitute the first direct evidence for the generation of 1· and 2· from 1, provide insights into the mechanism of DNA cleavage by 1.
（-）-洛马维替辛 A（1）是一种 C 对称细胞毒素，含有两个重氮芴官能团，并诱导 DNA 双链断裂（DSB）。有证据表明，DNA 断裂是由脱氧核糖骨架上的氢原子提取引发的。在这里，我们通过硫醇对重氮芴的 1,7-加成反应，证明了 1 形成了乙烯基自由基 1·和 2·。这些自由基可以影响甲醇和丙酮中氢原子的提取。硫醇对 1 的第一次加成比第二次加成快得多。在 -50°C 下检测到在生成 1·的过程中形成的重氮亚砜 5，并在 -20°C 下在空气中以半衰期 110 分钟分解为 1·。这些数据构成了 1 生成 1·和 2·的第一个直接证据，为 1 切割 DNA 的机制提供了深入了解。
