Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity.
Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity.
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DOI：
10.1021/jm8013234
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发表时间：
2009-02-26
影响因子：
7.3
通讯作者：
Keppler BK
中科院分区：
文献类型：
--
作者：
Mendoza-Ferri MG;Hartinger CG;Mendoza MA;Groessl M;Egger AE;Eichinger RE;Mangrum JB;Farrell NP;Maruszak M;Bednarski PJ;Klein F;Jakupec MA;Nazarov AA;Severin K;Keppler BK
多核铂抗癌化合物是克服已有抗癌化合物耐药性的有效选择。将这一概念转移到Ru(II)-芳烃配合物中，合成了含有双(吡啶酮)烷烃连接体的双核Ru(II)-芳烃化合物。研究发现，间隔基长度对化合物的体外抗癌活性有显著影响，这与化合物的亲脂性有关。在人类肿瘤细胞系中发现了与已建立的铂类药物相同维度的IC50值。在三个耐药细胞系中，最活跃的复合体对顺铂前体药物奥施铂没有交叉耐药性；事实上，在两个耐药株中发现了10倍的敏感性逆转。对具有代表性的例子的(生物)分析表征表明，Ru络合物迅速水解，形成主要对转铁蛋白和DNA具有亲和力的二水物种，表明蛋白质和碱基都是潜在的目标。
Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)–arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC50 values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.
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DOI：
10.1016/1044-0305(91)85005-q
发表时间：
1991-09-01
影响因子：
3.2
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
Keppler, BK
DOI：
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发表时间：
2003-05-01
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
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作者：
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