Efficient and specific strand scission of DNA by a dinuclear copper complex: Comparative reactivity of complexes with linked tris(2-pyridylmethyl)amine moieties
Efficient and specific strand scission of DNA by a dinuclear copper complex: Comparative reactivity of complexes with linked tris(2-pyridylmethyl)amine moieties
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DOI：
10.1021/ja020039z
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发表时间：
2002-05-29
影响因子：
15
通讯作者：
Rokita, SE
中科院分区：
文献类型：
--
作者：
Humphreys, KJ;Karlin, KD;Rokita, SE
化合物[Cu-2（II）（D-1）（H2O）（2）]（ClO 4）（4）（D-1 =双核配体，两个三（2-吡啶基甲基）-胺单元在其5-吡啶基位置通过-CH 2 CH 2-桥共价连接）选择性地促进寡核苷酸链上DNA的切割，所述寡核苷酸链从磨损的双链体结构的3'侧延伸到距离连接点两个残基的位点。反应的最低要求包括在邻近切割位点的3'突出端的n（即第一个未配对的）位置上的鸟嘌呤和在5'突出端上的n位置上的腺嘌呤。识别和链断裂不依赖于切割位点处的核碱基。还原剂和分子氧两者的必要存在表明负责裂解的中间体是通过铜（I）形式的双核络合物活化分子氧产生的。缺乏自由基淬灭剂的敏感性和高水平的网站选择性断裂建议的机制，不涉及一个可扩散的自由基物种。与单核类似物[Cu-II（TMPA）-（H2O）]（ClO 4）（2）（TMPA =三（2-吡啶基甲基）胺）和[Cu（OP）（2）]（2+）（OP = 1，10-菲咯啉）在同等铜离子浓度下的作用相比，多金属中心表现出促进有效裂解的协同作用。双核配合物[Cu-2（II）（D-1）（H2O）（2）]（ClO 4）（4）甚至能够在[Cu（OP）（2）]（2+）不可检测地修饰DNA的浓度下介导有效的特异性链断裂。[Cu-2（II）（D-1）（H2O）（2）]（ClO 4）（4）的独特配位和反应性质对其效率和位点选择性至关重要，因为类似物[Cu-2（II）（DO）（Cl-2）]（ClO 4）（2）（其中DO是与D-1非常相似的双核配体，但具有-CH 2 OCH 2-桥）仅表现出非选择性的DNA切割。这两种复合物与DNA的反应性以及它们先前建立的与分子氧的相互作用的差异表明，特定的链断裂是反应性中间体的取向的函数。
The compound [Cu-2(II)(D-1)(H2O)(2)](ClO4)(4) (D-1 = dinucleating ligand with two tris(2-pyridylmethyl)-amine units covalently linked in their 5-pyridyl positions by a -CH2CH2- bridge) selectively promotes cleavage of DNA on oligonucleotide strands that extend from the 3' side of frayed duplex structures at a site two residues displaced from the junction. The minimal requirements for reaction include a guanine in the n (i.e. first unpaired) position of the 3' overhang adjacent to the cleavage site and an adenine in the n position on the 5' overhang. Recognition and strand scission are independent of the nucleobase at the cleavage site. The necessary presence of both a reductant and dioxygen indicates that the intermediate responsible for cleavage is produced by the activation of dioxygen by a copper(l) form of the dinuclear complex. The lack of sensitivity to radical quenching agents and the high level of site selectivity in scission suggest a mechanism that does not involve a diffusible radical species. The multiple metal center exhibits a synergy to promote efficient cleavage as compared to the action of a mononuclear analogue [Cu-II(TMPA)-(H2O)](ClO4)(2) (TMPA = tris(2-pyridylmethyl)amine) and [Cu(OP)(2)](2+) (OP = 1, 10-phenanthroline) at equivalent copper ion concentrations. The dinuclear complex, [Cu-2(II)(D-1)(H2O)(2)](ClO4)(4), is even capable of mediating efficient specific strand scission at concentrations where [Cu(OP)(2)](2+) does not detectably modify DNA. The unique coordination and reactivity properties of [Cu-2(II)(D-1)(H2O)(2)](ClO4)(4) are critical for its efficiency and site selectivity since an analogue, [Cu-2(II)(DO)(Cl-2)](ClO4)(2), where DO is a dinucleating ligand very similar to D-1, but with a -CH2OCH2- bridge, exhibits only nonselective cleavage of DNA. The differences in the reactivity of these two complexes with DNA and their previously established interaction with dioxygen suggest that specific strand scission is a function of the orientation of a reactive intermediate.