Structure and unique interactions with DNA of a cationic trans-platinum complex with the nonplanar bicyclic piperidinopiperidine ligand.
Structure and unique interactions with DNA of a cationic trans-platinum complex with the nonplanar bicyclic piperidinopiperidine ligand.
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DOI：
10.1002/anie.200462389
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发表时间：
2005-05
影响因子：
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通讯作者：
Y. Najajreh;D. Prilutski;Yael Ardeli-Tzaraf;J. Pérez;E. Khazanov;Y. Barenholz;J. Kašpárková;V. Br
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文献类型：
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作者：
Y. Najajreh;D. Prilutski;Yael Ardeli-Tzaraf;J. Pérez;E. Khazanov;Y. Barenholz;J. Kašpárková;V. Br
方形平面铂（ii）配合物与细胞DNA共价结合并扭曲其结构的能力对全世界许多癌症患者的生活产生了压倒性的影响。抗癌药物顺铂（图1a）通过与同一DNA链上相邻的两个鸟嘌呤残基共价结合（1,2 - gpg交联）发挥其细胞毒性作用，随后DNA扭曲，触发导致癌细胞死亡的细胞过程。[1,2]顺铂的两个关键特性使其成为一种有效的抗癌剂，一是它的惰性，使它能够在通往DNA的细胞外液和细胞内液中大量嗜铂细胞的冲击下存活下来，二是它能够扭曲DNA。[3,4]顺铂是一种非常有效的抗癌药物，但肿瘤对该药物产生耐药性的能力影响了其临床成功。试图克服顺铂获得性耐药性的一种方法是制备具有反式结构的铂（ii）复合物，这种复合物不能结合同一条链上相邻的两个鸟嘌呤，因此它们最终会与DNA形成其他病变，并以不同于顺铂的方式扭曲DNA。移植本身（图1b）不具有细胞毒性，然而，几种具有平面杂环胺配体、大体积脂肪胺配体或亚胺醚配体或非平面杂环胺配体的反铂配合物显示出各种DNA结合特性以及令人印象深刻的细胞毒性。[5-11]我们最近报道了与哌嗪（pz）和哌啶（pip）配体的反式铂配合物的制备、细胞毒性和dna结合特性（图1c和d），这些配合物在人卵巢癌细胞系中绕过了顺铂耐药性。[12,13]选择哌嗪作为配体是因为我们想要一种可溶的、阳离子的反式铂配合物，它不仅能共价修饰DNA，而且配体本身还能在PtII修饰位点移除的第二个位点与DNA相互作用。作为这一理论基础的自然延伸，我们最近制备了复合物trans-[PtCl2 (NH3)(pip-pip)]·HCl(1),[14]，现在我们报告了它的x射线晶体结构和一些dna结合和药理学性质。通过从水溶液中缓慢蒸发得到x射线质量的晶体（图2a）两个哌啶环的构象以及分子尺寸如图2b所示。在结构上，我们可以将分子分为三部分：1)铂（ii）配位球，2)第一个哌啶环，3)第二个哌啶环。铂的键长PtÀCl在2.30左右，键长PtÀN在2.06左右，形成了通常的方平面配位几何。
The ability of square-planar platinum (ii) complexes to covalently bind to cellular DNA and distort its structure has had an overwhelming impact on the lives of many cancer patients worldwide. The anticancer drug cisplatin (Figure 1 a), exerts its cytotoxic effect by binding covalently to two adjacent guanine residues on the same DNA strand (1, 2-GpG cross-link), and the ensuing distortion of the DNA, triggers cellular processes that lead to the death of the cancer cell.[1, 2] The two crucial properties of cisplatin that make it an efficient anticancer agent are its inertness that enables it to survive the onslaught of the plethora of platinophiles in the extra-and intracellular fluids on the way to the DNA, and its ability to distort the DNA.[3, 4] Cisplatin is an extremely effective anticancer agent, whose clinical success is marred by the ability of tumors to acquire resistance to the drug. One approach to try and overcome the acquired resistance to cisplatin was to prepare platinum (ii) complexes having trans geometry that are incapable of binding two adjacent guanines on the same strand, so they end up forming other lesions with the DNA and distort it differently than cisplatin. Transplatin itself (Figure 1 b) is not cytotoxic, yet, several classes of transplatinum complexes with planar heterocyclic amine ligands, bulky aliphatic amine ligands or iminoether ligands, or nonplanar heterocyclic amine ligands have displayed a variety of DNA binding properties as well as impressive cytotoxic properties.[5–11]We have recently reported on the preparation, cytotoxicity and the DNA-binding properties of trans-platinum complexes with piperazine (pz) and piperidine (pip) ligands (Figure 1c and d), which circumvent cisplatin resistance in human ovarian cancer cell lines.[12, 13] Piperazine was selected as a ligand because we wanted a soluble, cationic, trans-platinum complex that will not only covalently modify the DNA, but in addition, the ligand itself will interact with the DNA at a second site which is removed from the PtII modification site. As a natural extension of this rationale, we have recently prepared the complex trans-[PtCl2 (NH3)(pip-pip)]· HCl (1),[14] and now we report its X-ray crystal structure and some of its DNA-binding and pharmacological properties. X-ray quality crystals were obtained by slow evaporation from aqueous solution (Figure 2a).[15] The conformation of the two piperidine rings together with the molecular dimensions are depicted in Figure 2b. Structurally, we can divide the molecule into three parts: 1) the platinum (ii) coordination sphere, 2) the first piperidine ring, and 3) the second piperidine ring. The platinum forms the usual square-planar coordination geometry with the PtÀCl bond lengths around 2.30 and the PtÀN bonds around 2.06.