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首页> 外文期刊>Chemistry: A European journal >Mitochondrial mode of action of a thymidine-based cisplatin analogue breaks resistance in cancer cells
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Mitochondrial mode of action of a thymidine-based cisplatin analogue breaks resistance in cancer cells

机译：基于胸苷的顺铂类似物的线粒体作用方式破坏了癌细胞的耐药性

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Cisplatin analogue complexes with platinum(II) and palladium(II) starting from 3′,5′-diamino-3′,5′-dideoxy-thymidines were synthesized, both with the D-erythro- and D-threo configurations. Complexes of the general formula [MCl2L] were obtained and characterized. NMR spectroscopic measurements and single crystal X-ray structure analysis showed that the metal centers are coordinated to the ligands by the amino groups in 3′- and 5′-positions and not through the thymine moiety. All ligands and complexes showed no significant in vitro activities except thymiplatin (cis-dichloro(3′,5′-diamino-3′,5′-dideoxy-D-threo- thymidine)platinum(II)). Detailed in vitro studies on the apoptosis pathway in lymphoma (BJAB), leukemia (NALM-6), and melanoma cells (Mel-HO) as well as on transfected or resistant cell lines were carried out. Thymiplatin significantly induced an apoptotic response, which was found to be associated with the loss of mitochondrial membrane potential and with caspase activation. The activity was shown to be independent of Fas-associated protein with death domain (FADD), but dependent on Bcl-2 expression. As a consequence, for thymiplatin a mitochondrial mode of action could be assigned. Moreover, the compound showed activity in cells resistant to common drugs, such as daunorubicin and vincristin, and showed synergistic effects with doxorubicin, vincristin, cytarabin, and daunorubicin. Prove your metal: Cisplatin analogues with platinum(II) and palladium(II) complexes based on 3′,5′-diamino thymidines were synthesized (see figure for an example) and one was found to induce apoptosis mediated by caspase-9 and -3 processing. Thymiplatin was proven to be active on cisplatin, vincristin and daunorubicin resistant leukemia cells, and was synergistic with cytarabin, vincristin, daunorubicin, and doxorubicin in lymphoma cells.
机译：合成了具有D-赤型和D-苏型构型的以3'，5'-二氨基-3'，5'-二脱氧胸苷为原料的具有铂（II）和钯（II）的顺铂类似物复合物。获得并表征了通式[MCl 2 L]的配合物。 NMR光谱测量和单晶X射线结构分析表明，金属中心通过3'-和5'-位的氨基而不是通过胸腺嘧啶部分与配体配位。除胸苷铂（顺-二氯（3'，5'-二氨基-3'，5'-二脱氧-D-苏-胸苷）铂（II））外，所有配体和复合物均无明显的体外活性。对淋巴瘤（BJAB），白血病（NALM-6）和黑素瘤细胞（Mel-HO）以及转染或耐药细胞系的凋亡途径进行了详细的体外研究。胸腺铂显着诱导凋亡反应，发现其与线粒体膜电位的丧失和胱天蛋白酶的活化有关。显示该活性独立于具有死亡结构域的FAS相关蛋白（FADD），但依赖于Bcl-2表达。结果，对于胸苷，可以指定线粒体的作用方式。此外，该化合物在对常见药物如柔红霉素和长春新碱具有抗性的细胞中显示活性，并显示出与阿霉素，长春新霉素，cytarabin和柔红霉素的协同作用。证明您的金属：合成了基于3'，5'-二氨基胸苷的具有铂（II）和钯（II）配合物的顺铂类似物（请参见示例），发现一个可以诱导由caspase-9和-介导的细胞凋亡。 3加工。胸腺素被证明对顺铂，长春新碱和柔红霉素耐药的白血病细胞有活性，并且与淋巴瘤细胞中的cytarabin，长春新素，柔红霉素和阿霉素具有协同作用。

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