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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >DNA fragment conformations in adducts with Kiteplatin
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DNA fragment conformations in adducts with Kiteplatin

机译：Kiteplatin加合物中的DNA片段构象

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The anticancer activity of cisplatin is triggered by its formation of intrastrand adducts involving adjacent G residues of DNA. To obtain information on the different conformers that can be formed, carrier ligands such as 2,2'-bipiperidine, which provide large steric bulk near the platinum coordination plane and decrease the dynamic motion about the Pt-N7 bonds, were introduced (" retro-modelling" approach). In the present study we investigate the effect of cis-1,4-diaminocyclohexane (cis-1,4-DACH) on the formation, stability, and stereochemistry of (cis-1,4-DACH) Pt(ss-oligo) adducts (ss-oligo = d(GpG) with 3'-and/or 5'-substituents). Interesting features of this ligand, absent in previous retro-modelling studies, include the large bite angle (expected to impede the ease of interconversion between possible conformers), the presence of two protons on each nitrogen (a characteristic associated with antitumor activity), and the absence of chiral centres. The use of cis-1,4-DACH has made it possible to detect different conformers in a system containing a primary diamine carrier ligand associated with anticancer activity and to confirm the previous hypothesis that the coexistence of different conformers established in studies of retro models having relatively bulky ligands is not an artefact resulting from carrier-ligand bulk. Moreover, the data for the (cis-1,4-DACH) Pt(d(GpG)) and (cis-1,4-DACH) Pt(d(GGTTT)) adducts indicate that at a temperature close to the physiological one (40 degrees C) HH1 and.HT1 conformers are present in comparable amounts. In contrast, at low temperature (close to 0 degrees C) the equilibrium shifts dramatically toward the more stable HH1 conformer (for the (cis-1,4-DACH) Pt(d(TGGT)) adduct the HH1 conformer is always dominant, even at high temperature). Notably, (cis-1,4-DACH) PtCl2 (Kiteplatin) has been recently reinvestigated and found to be particularly active against colorectal cancer (including oxaliplatin-resistant phenotypes).
机译：顺铂的抗癌活性是由其形成的涉及DNA相邻G残基的链内加合物触发的。为了获得有关可能形成的构象异构体的信息，引入了载体配体，例如2,2'-联哌啶，它们在铂配位平面附近提供了较大的空间体积，并降低了围绕Pt-N7键的动态运动（“ -建模”方法）。在本研究中，我们研究了顺式1,4-二氨基环己烷（cis-1,4-DACH）对（cis-1,4-DACH）Pt（ss-oligo）加合物的形成，稳定性和立体化学的影响（具有3'和/或5'取代基的ss-oligo = d（GpG））。该配体的有趣特征（以前的建模研究中没有）包括较大的咬合角（预期会阻碍可能的构象异构体之间的相互转化），每个氮原子上存在两个质子（与抗肿瘤活性相关的特征）和没有手性中心。 cis-1,4-DACH的使用使得在含有与抗癌活性相关的伯二胺载体配体的系统中检测不同构象异构体成为可能，并证实了先前的假设，即在具有相对大体积的配体不是由载体-配体体积产生的假象。此外，（顺1,4-DACH）Pt（d（GpG））和（顺1,4-DACH）Pt（d（GGTTT））加合物的数据表明，在接近生理温度的温度下（40摄氏度）HH1和.HT1构象异构体的含量相当。相反，在低温（接近0摄氏度）下，平衡会朝着更稳定的HH1构象异构体急剧转移（对于（cis-1,4-DACH）Pt（d（TGGT））加合物，HH1构象异构体始终占主导地位，即使在高温下）。值得注意的是，最近对（cis-1,4-DACH）PtCl2（风筝铂）进行了重新研究，发现其对结直肠癌（包括对奥沙利铂耐药的表型）特别有效。

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