Antitumoral effects of mitochondria-targeting neutral and cationic cis-[bis(1,3-dibenzylimidazol-2-ylidene)Cl(L)]Pt(ii) complexes.
Antitumoral effects of mitochondria-targeting neutral and cationic cis-[bis(1,3-dibenzylimidazol-2-ylidene)Cl(L)]Pt(ii) complexes.
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DOI：
10.1039/d0dt01664k
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发表时间：
2020-06
影响因子：
4
通讯作者：
M. Rothemund;Sofia I. Bär;Tobias Rehm;H. Kostrhunová;V. Brabec;R. Schobert
中科院分区：
文献类型：
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作者：
M. Rothemund;Sofia I. Bär;Tobias Rehm;H. Kostrhunová;V. Brabec;R. Schobert
最近，我们开发了一种合成顺式-[（NHC）1（NHC）2 PtIICl（L）]型抗肿瘤铂配合物的方法，该配合物以与配合物电荷和离去氯基配体的空间可及性相关的方式与DNA相互作用。我们现在确定线粒体而不是细胞核是中性二氯基复合物1（L = Cl）和离域亲脂性阳离子膦复合物2（L = PPh 3）的细胞靶点，两者都携带相同的顺式-双（1，3-二苄基咪唑-2-亚基）配体。它们在518 A2黑色素瘤细胞中的摄取是浓度依赖性的，并且对于复合物2明显更大，复合物2也对敏感的癌细胞系具有更大的细胞毒性，具有亚微摩尔IC 50值。这两种复合物强烈干扰各种形式的DNA在体外，但只有复合物2引起黑色素瘤细胞周期停滞在G1期，设置除了S期阻滞药物顺铂。1和2的细胞内定位的研究进行了与它们的炔标记的类似物6和7，这表明相同的模式的癌细胞的细胞毒性，细胞周期干扰和对线粒体的影响。与7-羟基香豆素叠氮化物的点击反应、与Mitotracker™的共定位和共聚焦显微术证明复合物6和7主要在黑色素瘤细胞的线粒体而不是细胞核中积累。复合物1和复合物2降低了线粒体膜电位，也增加了细胞ROS水平。因此，这两种复合物引起的应力纤维形成的F-肌动蛋白细胞骨架的黑色素瘤细胞，最明显的是复合物2，也激活了凋亡级联介导的半胱天冬酶-3和-7。
Recently, we opened a synthetic access to antitumoral platinum complexes of the type cis-[(NHC)1(NHC)2PtIICl(L)] which interact with DNA in a way correlated to the complex charge and to the sterical accessibility of the leaving chlorido ligand. We now identified mitochondria rather than nuclei as the cellular target of the neutral dichlorido complex 1 (L = Cl) and the delocalized lipophilic cationic phosphine complex 2 (L = PPh3), both carrying the same cis-bis(1,3-dibenzylimidazol-2-ylidene) ligands. Their uptake into 518A2 melanoma cells was concentration-dependent and distinctly greater for complex 2 which was also more cytotoxic against sensitive cancer cell lines with submicromolar IC50 values. Both complexes interfered strongly with various forms of DNA in vitro, but only complex 2 caused a melanoma cell cycle arrest in G1-phase, setting both apart from the S-phase arresting drug cisplatin. Studies of the intracellular localisation of 1 and 2 were carried out with their alkyne-tagged analogues 6 and 7, which showed identical patterns of cancer cell cytotoxicity, cell cycle interference and effects on mitochondria. Click reactions with 7-hydroxycoumarin azide, colocalisation with Mitotracker™ and confocal microscopy, proved complexes 6 and 7 to accumulate mainly in the mitochondria rather than the nuclei of melanoma cells. Complex 1 and even more so complex 2 reduced the mitochondrial membrane potential and also increased the cellular ROS levels. As a consequence, both complexes caused stress fibre formation in the F-actin cytoskeleton of melanoma cells, most distinctly so complex 2 which also activated the apoptotic cascade mediated by capases-3 and -7.