New minor groove covering DNA binding mode of dinuclear Pt(II) complexes with various pyridine-linked bridging ligands and dual anticancer-antiangiogenic activities
New minor groove covering DNA binding mode of dinuclear Pt(II) complexes with various pyridine-linked bridging ligands and dual anticancer-antiangiogenic activities
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DOI：
10.1007/s00775-020-01770-7
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发表时间：
2020-05-01
影响因子：
3
通讯作者：
Rajkovic, Snezana
中科院分区：
文献类型：
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作者：
Franich, Andjela A.;Zivkovic, Marija D.;Rajkovic, Snezana
新的抗癌铂（II）化合物同时靶向肿瘤细胞和肿瘤源性新血管生成，具有新的DNA相互作用模式和大的治疗窗口，是提高临床铂类化疗药物疗效的有吸引力的替代方案。本文报道了三种新型的双核[{Pt（en）Cl}（2）（μ-L）]（2+）配合物，它们分别与4，4 '-联吡啶（Pt 1）、1，2-联吡啶（Pt 2）、1，2-联吡啶（Pt 3）、1，2-联吡啶（Pt 4）、1，2-联吡啶（Pt 3）、1，4-联吡啶（Pt 4）、1，2-联吡啶（Pt 3）、1，2-联（4-吡啶基）乙烷（Pt 2）和1，2-双（4-吡啶基）乙烯（Pt 3），其高度带正电荷的水衍生物，[{Pt（en）（H2O）}（2）（μ-L）]（4+），与磷酸骨架相互作用，形成DNA-Pt加合物，具有独特的和以前未描述的结合模式，称为小沟覆盖。本研究结果表明，这种新的结合模式的水铂（II）配合物与DNA可以归因于其氯化物类似物的较高的抗癌活性。所有三种化合物，特别是络合物[{Pt（en）Cl}（2）（mu-4，4 '-bipy）]Cl-2中心点2 H（2）O（4，4'-bipy是4，4 '-bipyridine）（Pt 1），在斑马鱼-小鼠黑色素瘤异种移植模型中克服了体内顺铂抗性，显示出比抗血管生成药物苹果酸舒尼替尼高得多的治疗潜力，同时有效地阻断肿瘤新血管形成和黑色素瘤细胞转移。总体治疗概况表明，新的双核铂（II）配合物可能是新的，有效的和安全的抗癌药物。最后，与这些配合物的结构特征的相关性可以作为开发新的和更有效的抗癌药物的有用工具。
New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl}(2)(mu-L)](2+) complexes with different pyridine-like bridging ligands (L), 4,4 '-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H2O)}(2)(mu-L)](4+), interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl}(2)(mu-4,4 '-bipy)]Cl-2 center dot 2H(2)O (4,4 '-bipy is 4,4 '-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish-mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs.