Abstract

Arylamines are known to form covalent-DNA adducts upon metabolic activation. These covalent adducts adopt different conformational attributes, viz., major groove (B), stacked (S), and minor groove (W), and lead to different types of mutations. The conformation depends on the flanking and next flanking bases at the 3′ position of the adduct. Early detection of these conformations by simple probes is an ideal and challenging task. Here, we have reported two Ir(III)-based cyclometalated complexes, viz., [Ir(ppy)₂(imiphen)]⁺ (1) (ppy: 2-phenylpyridine; imiphen: 2-(1H-imidazol-2-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)₂(furphen)]⁺ (2) (furphen: 2-(furan-2-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its interaction with N-acetyl-2-aminofluorene-dG (AAF-dG). The sequences used in this work are NarI sequence (–CG₁G₂CG₃CX–) in which Gs are modified with AAF and X is either C or T. Luminescence studies reveal that the Ir(III) complexes bind to AAF-dG adduct with high specificity toward G₁ and G₃ compared to G₂ and unmodified control. The selectivity also depends on the next flanking base as cytosine favors G₃^AAF, while thymine favors G₁^AAF in complex 1 and vice versa for complex 2. The quenching studies confirm that Ir(III) complexes bind with AAF-dG sequences through the minor groove. The outcome of this work reveals that the switch-on effect by the complexes can be utilized for determining the conformational heterogeneity of the adduct and also for similar covalent-DNA adducts.

Graphic abstract

中文翻译：

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环金属化 Ir(III) 配合物对构象特异性芳胺-DNA 加合物的开启效应。

摘要

已知芳胺在代谢活化时形成共价 DNA 加合物。这些共价加合物采用不同的构象属性，即大沟 ( B )、堆叠 ( S ) 和小沟 ( W )，并导致不同类型的突变。构象取决于加合物 3' 位置的侧翼和下一个侧翼碱基。通过简单的探针及早检测这些构象是一项理想且具有挑战性的任务。在这里，我们报道了两种基于 Ir(III) 的环金属化配合物，即 [Ir(ppy) ₂ (imiphen)] ⁺ ( 1 ) (ppy: 2-phenylpyridine; imiphen: 2-(1 H -imidazol -2 -yl)-1 H -咪唑并[4,5- f][1,10] 菲咯啉) 和 [Ir(ppy) ₂ (furphen)] ⁺ ( 2 ) (furphen: 2-(furan-2-yl)-1 H -imidazo[4,5- f ][1, 10]菲咯啉）及其与N-乙酰基-2-氨基芴-dG (AAF-dG) 的相互作用。这项工作中使用的序列是Nar I 序列 (–CG ₁ G ₂ CG ₃ CX–)，其中 Gs 被 AAF 修饰，X 是 C 或 T。发光研究表明 Ir(III) 复合物与 AAF-结合dG的加合物与向g高特异性₁和G ₃相比至G ₂和未修改的控制。选择性还取决于下一个侧翼碱基，因为胞嘧啶有利于 G ₃ ^AAF，而胸腺嘧啶有利于复合物1 中的G ₁ ^AAF，对于复合物2反之亦然。淬灭研究证实 Ir(III) 复合物通过小沟与 AAF-dG 序列结合。这项工作的结果表明，复合物的开启效应可用于确定加合物的构象异质性，也可用于类似的共价 DNA 加合物。

图形摘要