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(μ-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(μ-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(μ-4,4′-bipy)]Cl₂·2H₂O (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.

中文翻译：

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新的小沟覆盖双核Pt（II）配合物与各种吡啶连接的桥联配体和双重抗癌-抗血管生成活性的DNA结合模式。

新的抗癌铂（II）化合物同时靶向肿瘤细胞和肿瘤衍生的新血管生成，具有新的DNA相互作用模式和宽大的治疗窗口，是提高临床铂化学疗法疗效的诱人选择。在这里，我们描述了三种新型双核[{Pt（en）Cl} ₂（μ- L）] ²⁺配合物，它们具有不同的吡啶样桥联配体（L），4,4'-联吡啶（Pt1），1,2-双（4-吡啶基）乙烷（P t2中）和1,2-双（4-吡啶基）乙烯（PT3） ，其高度，带正电荷的AQUA衍生物，[{铂（烯）（H ₂ O）} ₂（μ - L）] ⁴⁺，与磷酸盐骨架形成相互作用的DNA-Pt加合物，具有独特的，以前未描述的结合方式，称为小沟覆盖。这项研究的结果表明，aqua-Pt（II）复合物与DNA的新结合模式可能归因于其氯化物类似物的更高的抗癌活性。所有这三种化合物，特别是复杂的[{Pt（en）Cl} ₂（μ - 4,4'-bipy ）] Cl ₂ ·2H ₂ O（4,4'-bipy是4,4'-联吡啶）（Pt1） ，在斑马鱼-小鼠黑素瘤异种移植模型中克服了体内顺铂耐药性，显示出比抗血管生成药物苹果酸舒尼替尼更高的治疗潜力，同时有效地阻断了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Pt（II）复合物可能是新颖，有效和安全的抗癌药。最后，与这些复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。