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首页> 外文期刊>Chemistry: A European journal >Solution Behaviour and Biomolecular Interactions of Two Cytotoxic trans-Platinum(II) Complexes Bearing Aliphatic Amine Ligands
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Solution Behaviour and Biomolecular Interactions of Two Cytotoxic trans-Platinum(II) Complexes Bearing Aliphatic Amine Ligands

机译：两种带有脂肪胺配体的细胞毒性反铂（II）配合物的溶液行为和生物分子相互作用

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摘要

A novel trans-platinum(II) complex bearing one dimethylamine (dma) and one methylamine (ma) ligand, namely trans-[PtCl2ACHTUNGTRENUNG dma)(ma)], recently synthesised and characterised in our laboratory, displayed relevant antiproliferative properties in vitro, being more active than the parent complex, trans-[PtCl2ACHTUNGTRENUNG(dma) CHTUNGTRENUNG(ipa)], which has isopropylamine (ipa) in place of methylamine. We have analysed comparatively the solution behaviour of these two complexes under various experimental conditions, and investigated their reactivity with horse heart cytochrome c by mass spectrometry, inductively coupled plasma–optical emission spectroscopy (ICP-OES), 2D [1H,15N],ACHTUNGTRENUNG[1H,13C] HSQC and [1H,1H] NOESY NMR. Some important changes that occurred in the [1H,13C] HSQC NMR spectrum of cytochrome c treated with trans-[PtCl2ACHTUNGTRENUNG(dma) ma)] in water, after two daysincubation, most probably arose from direct platinum coordination to the protein side chain; this was proved conclusively by [1H,1H] NOESY NMR and [1H,15N] HSQC NMR measurements. Met65 was identified as the primary Pt binding site on cytochrome c. Electrospray mass spectrometry (ESIMS) results provided evidence for extensive platinum–protein adduct formation. A fragment of the [PtACHTUNGTRENUNG(amine)ACHTUNGTRENUNG(amine’)] type was established to be primarily responsible for protein metalation. ICP-OES analysis revealed that these trans-platinum(II) complexes bind preferentially to the serum proteins albumin and transferrin rather than to calf thymus DNA. Pt binding to DNA was found to be far lower than in the case of cisplatin. The implications of the results for the mechanism of action of novel cytotoxic trans-platinum complexes are discussed.
机译：最近在我们的实验室中合成并表征了一种新型的带有一个二甲胺（dma）和一个甲胺（ma）配体的反铂（II）复合物，该化合物在体外具有一定的抗增殖特性，反式-[PtCl2ACHTUNGTRENUNG（dma）CHTUNGTRENUNG（ipa）]比母体复合物更具活性，它用异丙胺（ipa）代替了甲胺。我们已经比较地分析了这两种配合物在各种实验条件下的溶解行为，并通过质谱，电感耦合等离子体-光发射光谱法（ICP-OES），二维[1H，15N]，ACHTUNGTRENUNG研究了它们与马心脏细胞色素c的反应性。 [1H，13C] HSQC和[1H，1H] NOESY NMR。在水中孵育两天后，在水中用反式[PtCl2ACHTUNGTRENUNG（dma）ma）处理的细胞色素c的[1H，13C] HSQC NMR光谱中发生了一些重要变化，最有可能是由直接的铂配位到蛋白质侧链引起的。这已通过[1H，1H] NOESY NMR和[1H，15N] HSQC NMR确证。 Met65被确定为细胞色素c上的主要Pt结合位点。电喷雾质谱（ESIMS）结果为广泛的铂-蛋白质加合物形成提供了证据。建立了[PtACHTUNGTRENUNG（amine）ACHTUNGTRENUNG（amine'）]类型的片段，主要负责蛋白质金属化。 ICP-OES分析表明，这些反式铂（II）配合物优先结合血清蛋白白蛋白和转铁蛋白，而不是小牛胸腺DNA。发现与DNA结合的Pt远低于顺铂的情况。讨论了结果对新型细胞毒性反铂复合物作用机理的影响。

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