Chemistry Department, 6 University Ave., Acadia University, Wolfville, Canada.
Bioorg Med Chem. 2011 Jun 1;19(11):3357-60. doi: 10.1016/j.bmc.2011.04.043. Epub 2011 Apr 29.
The natural product jadomycin B, isolated from Streptomyces venezeulae ISP5230, has been found to cleave DNA in the presence of Cu(II) ions without the requirement for an external reducing agent. The efficiency of DNA cleavage was probed using supercoiled plasmid DNA in buffered solution as a model environment. EC₅₀ and t(½) values for cleavage were 1.7 μM and 0.75 h, respectively, and varied ± 5% with the particular batch of plasmid and jadomycin employed. While UV-vis spectroscopy indicates that the cleavage event does not involve direct binding of jadomycin B to DNA, a stoichiometric Cu(II) preference for optimum cleavage suggests a weak binding interaction between jadomycin B and Cu(II) in the presence of DNA. The Cu(II)-mediated cleavage is greatly enhanced by UV light, which implicates the jadomycin B radical cation and Cu(I) as potential intermediates in DNA cleavage. Evidence in favor of this hypothesis was derived from a mechanistic assay which showed reduced cleavage as a function of added catalase and EDTA, scavengers of H₂O₂ and Cu(II), respectively. Thus, jadomycin B may serve as a source of electrons for Cu(II) reduction, producing Cu(I) which reacts with H₂O₂ to form hydroxyl radicals that cause DNA strand scission. In addition, scavengers of hydroxyl radicals and superoxide also display inhibitory effects, underscoring the ability of jadomycin B to produce a powerful arsenal of deleterious oxygen species when copper is present.
天然产物杰多霉素 B 从委内瑞拉链霉菌 ISP5230 中分离出来，在 Cu(II)离子存在的情况下无需外部还原剂即可切割 DNA。使用缓冲溶液中的超螺旋质粒 DNA 作为模型环境来探测 DNA 切割的效率。EC₅₀ 和 t(½)值分别为 1.7 μM 和 0.75 h，并且与所使用的特定批次的质粒和杰多霉素的变化±5%。虽然紫外可见光谱表明切割事件不涉及杰多霉素 B 与 DNA 的直接结合，但 Cu(II)的化学计量偏好表明在 DNA 存在下杰多霉素 B 和 Cu(II)之间存在弱结合相互作用。Cu(II)介导的切割被紫外光大大增强，这表明杰多霉素 B 自由基阳离子和 Cu(I)可能是 DNA 切割的潜在中间体。支持这一假设的证据来自于一种机制测定，该测定显示随着添加过氧化氢和 Cu(II)的分别清除剂——过氧化氢酶和 EDTA 的加入，切割减少。因此，杰多霉素 B 可以作为 Cu(II)还原的电子源，产生与 H₂O₂反应形成导致 DNA 链断裂的羟基自由基的 Cu(I)。此外，羟基自由基和超氧自由基的清除剂也显示出抑制作用，这强调了当存在铜时，杰多霉素 B 能够产生强大的有害氧物质的能力。
