Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Inorg Chem. 2011 Jul 18;50(14):6626-36. doi: 10.1021/ic200512m. Epub 2011 Jun 13.
Platinum anticancer drug DNA intrastrand cross-link models, LPt(d(GpG)) (G* = N7-platinated G residue, L = R(4)dt = bis-3,3'-(5,6-dialkyl)-1,2,4-triazine), and R = Me or Et), undergo slow Pt-N7 bond rotation. NMR evidence indicated four conformers (HH1, HH2, ΔHT1, and ΛHT2); these have different combinations of guanine base orientation (head-to-head, HH, or head-to-tail, HT) and sugar-phosphodiester backbone propagation relative to the 5'-G* (the same, 1, or opposite, 2, to the direction in B DNA). In previous work on LPt(d(GpG)) adducts, Pt-N7 rotation was too rapid to resolve conformers (small L with bulk similar to that in active drugs) or L was too bulky, allowing formation of only two or three conformers; ΛHT2 was not observed under normal conditions. The (R(4)dt)Pt(d(GpG)) results support our initial hypothesis that R(4)dt ligands have Goldilocks bulk, sufficient to slow G* rotation but insufficient to prevent formation of the ΛHT2 conformer. Unlike the (R(4)dt)Pt(5'-GMP)(2) adducts, ROESY spectra of (R(4)dt)Pt(d(GpG)) adducts showed no EXSY peaks, a result providing clear evidence that the sugar-phosphodiester backbone slows conformer interchange. Indeed, the ΛHT2 conformer formed and converted to other conformers slowly. Bulkier L (Et(4)dt versus Me(4)dt) decreased the abundance of the ΛHT2 conformer, supporting our initial hypothesis that steric crowding disfavors this conformer. The (R(4)dt)Pt(d(GpG)) adducts have a low abundance of the ΔHT1 conformer, consistent with the proposal that the ΔHT1 conformer has an energetically unfavorable phosphodiester backbone conformation; its high abundance when L is bulky is attributed to a small d(GpG) spatial footprint for the ΔHT1 conformer. Despite the Goldilocks size of the R(4)dt ligands, the bases in the (R(4)dt)Pt(d(GpG)) adducts have a low degree of canting, suggesting that the ligand NH groups characteristic of active drugs may facilitate canting, an important aspect of DNA distortions induced by active drugs.
铂类抗癌药物 DNA 链内交联模型，LPt(d(GpG))(G*=N7-铂化 G 残基，L=R(4)dt=双-3,3'-(5,6-二烷基)-1,2,4-三嗪)，和 R=Me 或 Et)，经历缓慢的 Pt-N7 键旋转。NMR 证据表明有四种构象(HH1、HH2、ΔHT1 和 ΛHT2)；这些构象具有不同的鸟嘌呤碱基取向(头对头，HH，或头对尾，HT)和相对于 5'-G*(相同，1，或相反，2，在 B DNA 中)的糖-磷酸二酯骨架传播的组合。在以前对 LPt(d(GpG))加合物的研究中，Pt-N7 旋转太快，无法分辨构象(小 L 具有与活性药物相似的体积)或 L 体积过大，只能形成两种或三种构象；在正常条件下未观察到 ΛHT2。(R(4)dt)Pt(d(GpG))的结果支持我们的初始假设，即 R(4)dt 配体具有恰到好处的体积，足以减缓 G的旋转，但不足以阻止 ΛHT2 构象的形成。与(R(4)dt)Pt(5'-GMP)(2)加合物不同，(R(4)dt)Pt(d(GpG*))加合物的 ROESY 谱没有 EXSY 峰，这一结果提供了明确的证据，表明糖-磷酸二酯骨架减缓了构象交换。事实上，ΛHT2 构象形成并缓慢转化为其他构象。体积较大的 L(Et(4)dt 与 Me(4)dt)降低了 ΛHT2 构象的丰度，支持我们的初始假设，即空间拥挤不利于这种构象。(R(4)dt)Pt(d(GpG))加合物中 ΔHT1 构象的丰度较低，这与 ΔHT1 构象具有不利的磷酸二酯骨架构象的观点一致；当 L 体积较大时，其丰度较高归因于 ΔHT1 构象的 d(GpG)空间足迹较小。尽管 R(4)dt 配体的大小恰到好处，但(R(4)dt)Pt(d(GpG))加合物中的碱基具有较低的倾斜度，这表明活性药物特征的配体 NH 基团可能促进倾斜，这是活性药物诱导的 DNA 扭曲的一个重要方面。
