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首页> 外文期刊>Chemistry: A European journal >Energetics, Conformation, and Recognition of DNA Duplexes Modified by Methylated Analogues of [PtCl(dien)](+)
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Energetics, Conformation, and Recognition of DNA Duplexes Modified by Methylated Analogues of [PtCl(dien)](+)

机译：[PtCl（dien）]（+）甲基化类似物修饰的DNA双链体的能量学，构象和识别

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摘要

In early studies of empirical structure-activity relationships, monodentate Pt-II complexes were considered to be biologically inactive. Examples of such inactive monodentate Pt-II compounds are [PtCl(dien)](+) (dien=diethylenetriamine) and [PtCl(NH3)(3)](+). DNA is considered the major biological target of platinum compounds. Thus, monodentate DNA binding of Pt-II compounds was previously expected to display insignificant biological effects because it was assumed to affect DNA conformation and downstream cellular processes markedly less than the cross-links of bifunctional Pt-II complexes. More recently it was shown that some monodentate Pt-II complexes do exhibit biological effects: the active monodentate Pt-II complexes commonly feature bulkier amine ligands than the hitherto used dien or NH3 groups. We were therefore interested in determining whether it simple but marked enhancement of the bulkiness of the dien ligand in monodentate [Pt(NO3)(dien)](+) by multiple methylation of this ligand affects the early phases in which platinum compounds exert their biological activity. More specifically, the goals of this study performed in cell-free media, were to determine how the modification of DNA duplexes by methylated analogues of [Pt(NO3)(dien)](+) affects their energetics and how the alterations of this biophysical parameter are reflected by the recognition of these duplexes by DNA polymerases and the DNA repair system. We have found that the impact of the methylation of [Pt(NO3)(dien)](+) on the biophysical properties of DNA (thermodynamic thermal, and conformational properties) and its biochemical processes (DNA polymerization and the repair of DNA adducts) is remarkable. Hence, we conclude that monodentate DNA binding of Pt-II compounds may considerably affect the biophysical properties of DNA and consequently downstream cellular processes as a result of a large increase in the bulkiness of the nonleaving ligands in this class of metal complex.
机译：在早期的经验结构-活性关系的研究中，单齿Pt-II复合物被认为是无生物活性的。这种无活性的单齿Pt-II化合物的例子是[PtCl（dien）]（+）（dien =二亚乙基三胺）和[PtCl（NH3）（3）]（+）。 DNA被认为是铂化合物的主要生物学靶标。因此，以前认为与Pt-II化合物的单齿DNA结合将显示微不足道的生物学效应，因为据认为它对DNA构象和下游细胞过程的影响明显小于双功能Pt-II复合物的交联。最近的研究表明，某些单齿Pt-II配合物确实表现出生物学效应：活性的单齿Pt-II配合物通常具有比迄今使用的二烯或NH3基团更大的胺配体。因此，我们有兴趣确定单齿[Pt（NO3）（dien）]（+）中二烯配体的多甲基化是否简单但显着增强了该配体的体积是否影响了铂化合物发挥其生物学作用的早期阶段。活动。更具体地说，这项研究的目标是在无细胞培养基中进行研究，以确定[Pt（NO3）（dien）]（+）的甲基化类似物对DNA双链体的修饰如何影响其能量，以及这种生物物理学的改变DNA聚合酶和DNA修复系统对这些双链体的识别反映了参数。我们发现[Pt（NO3）（dien）]（+）的甲基化对DNA的生物物理特性（热力学热和构象特性）及其生化过程（DNA聚合和DNA加合物的修复）的影响非常了不起因此，我们得出结论，由于这类金属络合物中非离去配体的体积大大增加，Pt-II化合物的单齿DNA结合可能会大大影响DNA的生物物理特性，进而影响下游细胞过程。

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