Polynuclear platinum complexes represent a unique structural class of DNA-binding agents of biological significance. They contain at least two platinum coordinating units bridged by a linker, which means that the formation of double-base lesions (cross-links) in DNA is possible. Here, we show that the lead compound, bifunctional [{trans-PtCl(NH₃)₂}₂μ-trans-Pt(NH₃)₂{H₂N(CH₂)₆NH₂}₂]⁴⁺ (Triplatin or BBR3464), forms in DNA specific double-base lesions which affect the biophysical and biochemical properties of DNA in a way fundamentally different compared to the analogous double-base lesions formed by two adducts of monofunctional chlorodiethylenetriamineplatinum(II) chloride (dienPt). We find concomitantly that translesion DNA synthesis by the model A-family polymerase, the exonuclease deficient Klenow fragment, across the double-base lesions derived from the intrastrand CLs of Triplatin was markedly less extensive than that across the two analogous monofunctional adducts of dienPt. Collectively, these data provide convincing support for the hypothesis that the central noncovalent tetraamine platinum linker of Triplatin, capable of hydrogen-bonding and electrostatic interactions with DNA and bridging the two platinum adducts, represents an important factor responsible for the markedly lowered tolerance of DNA double-base adducts of Triplatin by DNA polymerases.

中文翻译：

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来自抗肿瘤三核铂化合物交联的跨双碱基病变的跨病变DNA合成：引物延伸，构象和热力学研究†

多核铂络合物代表具有生物学意义的DNA结合剂的独特结构类别。它们包含至少两个由接头桥接的铂配位单元，这意味着可能在DNA中形成双碱基损伤（交联）。在这里，我们表明，铅化合物，双官能[{反式-PtCl（NH ₃）₂ } ₂ μ-反式-Pt（NH ₃）₂ {H ₂ N（CH ₂）₆ NH ₂ } ₂ ] ⁴⁺（Triplatin或BBR3464），其中影响的方式完全不同的与通过单官能chlorodiethylenetriamineplatinum两种加合物形成的类似的双基病变DNA的生物物理和生物化学性质的DNA特定的双基病变的形式（II）氯化物（dienPt）。我们同时发现，由Triplatin链内CL衍生的双碱基病灶中，由模型A系列聚合酶（核酸外切酶缺陷型Klenow片段）进行的跨病变DNA合成明显不如跨越dienPt的两个类似的单功能加合物。总的来说，这些数据为以下假设提供了令人信服的假说：三铂的中心非共价四胺铂胺连接体能够与DNA发生氢键和静电相互作用，并桥接两个铂加合物，是导致DNA双倍耐受性显着降低的重要因素。 DNA聚合酶产生的三基铂碱基加合物。