Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
Dalton Trans. 2009 Dec 28(48):10846-60. doi: 10.1039/b911542k. Epub 2009 Oct 13.
The reaction of the redox-active ligand, Hpyramol (4-methyl-2-N-(2-pyridylmethyl)aminophenol) with K(2)PtCl(4) yields monofunctional square-planar [Pt(pyrimol)Cl], PtL-Cl, which was structurally characterised by single-crystal X-ray diffraction and NMR spectroscopy. This compound unexpectedly cleaves supercoiled double-stranded DNA stoichiometrically and oxidatively, in a non-specific manner without any external reductant added, under physiological conditions. Spectro-electrochemical investigations of PtL-Cl were carried out in comparison with the analogue CuL-Cl as a reference compound. The results support a phenolate oxidation, generating a phenoxyl radical responsible for the ligand-based DNA cleavage property of the title compounds. Time-dependent in vitro cytotoxicity assays were performed with both PtL-Cl and CuL-Cl in various cancer cell lines. The compound CuL-Cl overcomes cisplatin-resistance in ovarian carcinoma and mouse leukaemia cell lines, with additional activity in some other cells. The platinum analogue, PtL-Cl also inhibits cell-proliferation selectively. Additionally, cellular-uptake studies performed for both compounds in ovarian carcinoma cell lines showed that significant amounts of Pt and Cu were accumulated in the A2780 and A2780R cancer cells. The conformational and structural changes induced by PtL-Cl and CuL-Cl on calf thymus DNA and phiX174 supercoiled phage DNA at ambient conditions were followed by electrophoretic mobility assay and circular dichroism spectroscopy. The compounds induce extensive DNA degradation and unwinding, along with formation of a monoadduct at the DNA minor groove. Thus, hybrid effects of metal-centre variation, multiple DNA-binding modes and ligand-based redox activity towards cancer cell-growth inhibition have been demonstrated. Finally, reactions of PtL-Cl with DNA model bases (9-Ethylguanine and 5'-GMP) followed by NMR and MS showed slow binding at Guanine-N7 and for the double stranded self complimentary oligonucleotide d(GTCGAC)(2) in the minor groove.
氧化还原活性配体 Hpyramol（4-甲基-2-N-（2-吡啶甲基）氨基苯酚）与 K2PtCl4 反应生成单核的平面正方形 [Pt（pyrimol）Cl]，PtL-Cl，通过单晶 X 射线衍射和 NMR 光谱对其结构进行了表征。在生理条件下，该化合物无需添加任何外部还原剂，即可以非特异性方式，定量且氧化切割超螺旋双链 DNA。与类似物 CuL-Cl 进行的光谱电化学研究作为参考化合物。结果支持酚盐氧化，生成酚氧自由基，负责标题化合物的配体基 DNA 切割性质。在各种癌细胞系中，对 PtL-Cl 和 CuL-Cl 进行了时间依赖性体外细胞毒性测定。化合物 CuL-Cl 克服了卵巢癌和小鼠白血病细胞系中的顺铂耐药性，并在其他一些细胞中具有额外的活性。铂类似物 PtL-Cl 也选择性地抑制细胞增殖。此外，在卵巢癌细胞系中对这两种化合物进行的细胞摄取研究表明，大量的 Pt 和 Cu 积聚在 A2780 和 A2780R 癌细胞中。PtL-Cl 和 CuL-Cl 在环境条件下对小牛胸腺 DNA 和 phiX174 超螺旋噬菌体 DNA 引起的构象和结构变化通过电泳迁移率测定和圆二色性光谱进行了跟踪。这些化合物诱导 DNA 广泛降解和解旋，同时在 DNA 小沟中形成单加合物。因此，已经证明了金属中心变化、多种 DNA 结合模式和配体基氧化还原活性对癌细胞生长抑制的混合效应。最后，PtL-Cl 与 DNA 模型碱基（9-乙基鸟嘌呤和 5'-GMP）的反应，通过 NMR 和 MS 显示在鸟嘌呤-N7 处缓慢结合，并且在小沟中双链自互补寡核苷酸 d（GTCGAC）（2）处结合。
