Adjusting the DNA Interaction and Anticancer Activity of Pt(II) N-Heterocyclic Carbene Complexes by Steric Shielding of the Trans Leaving Group.
Adjusting the DNA Interaction and Anticancer Activity of Pt(II) N-Heterocyclic Carbene Complexes by Steric Shielding of the Trans Leaving Group.
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DOI：
10.1021/acs.jmedchem.5b00896
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发表时间：
2015-07
影响因子：
7.3
通讯作者：
Julienne K. Muenzner;Tobias Rehm;B. Biersack;A. Casini;I. A. D. de Graaf;Pawida Worawutputtapong;A. Noor;R. Kempe;V. Brabec;J. Kašpárková;R. Schobert
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文献类型：
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作者：
Julienne K. Muenzner;Tobias Rehm;B. Biersack;A. Casini;I. A. D. de Graaf;Pawida Worawutputtapong;A. Noor;R. Kempe;V. Brabec;J. Kašpárková;R. Schobert
五铂（II）配合物轴承（1，3-二苄基）咪唑-2-亚基配体，但不同的离去基团反式它的细胞毒性，DNA和细胞周期干扰，血管破坏性能，和肾毒性进行了检查。配合物3a-c的细胞毒性随着其离开氯配体的空间屏蔽而增加，并且具有两个三苯基膦的配合物3c是最有效的，具有亚微摩尔IC 50浓度。配合物3a-c在电泳迁移率变化和溴化乙锭结合试验中与DNA相互作用。阳离子复合物3c不与DNA配位结合，但导致其聚集，这是不适合于通常的修复机制的损伤。因此，它将黑色素瘤细胞的细胞周期阻滞在G1期，而顺式-二氯[（1，3-二苄基）咪唑-2-亚基]（二甲基亚砜）铂（II）3a诱导G2/M期阻滞。复合物3c还破坏了受精鸡蛋的绒毛尿囊膜中的血管。使用精确切割的组织切片的离体研究表明3a-c的肾毒性在临床上是可管理的。
Five platinum(II) complexes bearing a (1,3-dibenzyl)imidazol-2-ylidene ligand but different leaving groups trans to it were examined for cytotoxicity, DNA and cell cycle interference, vascular disrupting properties, and nephrotoxicity. The cytotoxicity of complexes 3a-c increased with the steric shielding of their leaving chloride ligand, and complex 3c, featuring two triphenylphosphanes, was the most efficacious, with submicromolar IC50 concentrations. Complexes 3a-c interacted with DNA in electrophoretic mobility shift and ethidium bromide binding assays. The cationic complex 3c did not bind coordinatively to DNA but led to its aggregation, damage that is not amenable to the usual repair mechanisms. Accordingly, it arrested the cell cycle of melanoma cells in G1 phase, whereas cis-dichlorido[(1,3-dibenzyl)imidazol-2-ylidene](dimethyl sulfoxide) platinum(II) 3a induced G2/M phase arrest. Complex 3c also disrupted the blood vessels in the chorioallantoic membrane of fertilized chicken eggs. Ex vivo studies using precision-cut tissue slices suggested the nephrotoxicities of 3a-c to be clinically manageable.