Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[PtIVCl4(NHC)2] complexes and their PtII precursors.
Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[PtIVCl4(NHC)2] complexes and their PtII precursors.
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DOI：
10.1039/c9dt02438g
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发表时间：
2019-11
影响因子：
4
通讯作者：
Tobias Rehm;M. Rothemund;T. Dietel;R. Kempe;R. Schobert
中科院分区：
文献类型：
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作者：
Tobias Rehm;M. Rothemund;T. Dietel;R. Kempe;R. Schobert
合成了4个新的双（N，N-二烷基苯并咪唑-2-亚基）二氯合铂（ii）配合物2，其N-烷基取代基（a：Me，B：Et，c：n-butyl，d：n-octyl）逐渐增大，并与PhICl 2氧化，得到相应的[PtIVCl 4（N，N-二烷基苯并咪唑-2-亚基）2]配合物4。已知的双（N，N-二苄基咪唑-2-亚基）二氯合铂（ii）配合物1同样被氧化成[PtIVCl 4（N，N-二苄基咪唑-2-亚基）2] 3。相反，用H_2O_2或次氯酸盐氧化配合物1和2，或在四氯配合物4中用氯交换羟基配体，都不能得到[PtIVCl_4-n（OH）n（NHC）_2]型可分离的配合物。在MTT试验中，[PtIICl 2（NHC）2]/[PtIVCl 4（NHC）2]复合物偶联1/3、2c/4c和反式-2c/反式-4c，带有N-苄基或N-丁基取代基，每种对至少三种人癌细胞系显示出相似的个位数微摩尔IC 50值，推测是由于PtIV复合物在细胞内还原成其活性PtII同源物。与顺铂不同，顺铂的抗癌作用需要功能性p53，它们中的每一种在野生型和p53阴性的HCT 116结肠癌细胞中都是活性的。在溴化乙锭饱和试验与分离的DNA，顺式-（双-NHC）PtII复合物，如1引起的形态DNA的变化比顺铂引发的更明显，而相应的顺式-（双-NHC）PtIV复合物，如3与DNA的相互作用，在一个较小的结构修饰的方式。
Four new bis(N,N-dialkylbenzimidazol-2-ylidene)dichlorido platinum(ii) complexes 2 featuring N-alkyl substituents of increasing size (a: Me, b: Et, c: n-butyl, d: n-octyl) were synthesised and oxidised with PhICl2 to give the corresponding [PtIVCl4(N,N-dialkylbenzimidazol-2-ylidene)2] complexes 4 as potential anticancer prodrugs. The known bis(N,N-dibenzylimidazol-2-ylidene)dichlorido platinum(ii) complex 1 was likewise oxidised to [PtIVCl4(N,N-dibenzylimidazol-2-ylidene)2] 3. In contrast, oxidation of complexes 1 and 2 with H2O2 or hypochlorites, or exchange of chlorido for hydroxo ligands in tetrachlorido complexes 4 failed to give isolable complexes of type [PtIVCl4-n(OH)n(NHC)2]. In MTT assays the [PtIICl2(NHC)2]/[PtIVCl4(NHC)2] complex couples 1/3, 2c/4c, and trans-2c/trans-4c, bearing either N-benzyl or N-butyl substituents, each showed similar single-digit micromolar IC50 values against at least three out of five human cancer cell lines, presumably due to an intracellular reduction of the PtIV complexes to their active PtII congeners. Unlike cisplatin, whose anticancer effect requires functional p53, each of them was active both in wildtype and in p53-negative HCT116 colon carcinoma cells. In ethidium bromide saturation assays with isolated DNA, cis-(bis-NHC)PtII complexes such as 1 caused morphological DNA changes more pronounced than those initiated by cisplatin, while the corresponding cis-(bis-NHC)PtIV complexes such as 3 interacted with DNA in a less structure-modifying way.