Malina Jaroslav, Farrell Nicholas P, Brabec Viktor
Institute of Biophysics, Academy of Sciences of the Czech Republic , v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Inorg Chem. 2014 Feb 3;53(3):1662-71. doi: 10.1021/ic402796k. Epub 2014 Jan 16.
The noncovalent analogues of antitumor polynuclear platinum complexes represent a structurally discrete class of platinum drugs. Their chemical and biological properties differ significantly from those of most platinum chemotherapeutics, which bind to DNA in a covalent manner by formation of Pt-DNA adducts. In spite of the fact that these noncovalent polynuclear platinum complexes contain no leaving groups, they have been shown to bind to DNA with high affinity. We report here on the DNA condensation properties of a series of noncovalent analogues of antitumor polynuclear platinum complexes described by biophysical and biochemical methods. The results demonstrate that these polynuclear platinum compounds are capable of inducing DNA condensation at more than 1 order of magnitude lower concentrations than conventional spermine. Atomic force microscopy studies of DNA condensation confined to a mica substrate have revealed that the DNA morphologies become more compact with increasing concentration of the platinum complexes. Moreover, we also found that the noncovalent polynuclear platinum complex {Pt(NH3)3}2-μ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2} (TriplatinNC-A) binds to DNA in a sequence-dependent manner, namely, to A/T-rich sequences and A-tract regions, and that noncovalent polynuclear platinum complexes protect DNA from enzymatic cleavage by DNase I. The results suggest that mechanisms of antitumor and cytotoxic activities of these complexes may be associated with their unique ability to condense DNA along with their sequence-specific DNA binding. Owing to their high cellular accumulation, it is also reasonable to suggest that their mechanism of action is based on the competition with naturally occurring DNA condensing agents, such as polyamines spermine, spermidine, and putrescine, for intracellular binding sites, resulting in the disturbance of the correct binding of regulatory proteins initiating the onset of apoptosis.
抗肿瘤多核铂配合物的非共价类似物代表了一类结构上独特的铂类药物。它们的化学和生物学性质与大多数铂类化疗药物有显著差异，后者通过形成Pt-DNA加合物以共价方式与DNA结合。尽管这些非共价多核铂配合物不含离去基团，但已证明它们能以高亲和力与DNA结合。我们在此报告一系列抗肿瘤多核铂配合物非共价类似物的DNA凝聚特性，采用生物物理和生化方法进行描述。结果表明，这些多核铂化合物能够在比传统精胺低一个多数量级的浓度下诱导DNA凝聚。对限制在云母基质上的DNA凝聚进行的原子力显微镜研究表明，随着铂配合物浓度的增加，DNA形态变得更加紧凑。此外，我们还发现非共价多核铂配合物{Pt(NH3)3}2-μ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}（TriplatinNC-A）以序列依赖的方式与DNA结合，即与富含A/T的序列和A-序列区域结合，并且非共价多核铂配合物能保护DNA免受DNase I的酶切。结果表明，这些配合物的抗肿瘤和细胞毒性活性机制可能与其凝聚DNA的独特能力以及序列特异性DNA结合有关。由于它们在细胞内的高积累，也有理由认为它们的作用机制是基于与天然存在的DNA凝聚剂（如多胺精胺、亚精胺和腐胺）竞争细胞内结合位点，从而导致启动细胞凋亡的调节蛋白正确结合受到干扰。
