MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
Sci Rep. 2013;3:2060. doi: 10.1038/srep02060.
A quaternized trigeminal ligand, 4-[4,6-di(4-pyridyl)-1,3,5-(2-triazinyl)]-1-methylpyridine-1-ium hexafluorophosphate (dptmp·PF6), and two derivative V-shaped dinuclear Pt(II) complexes, {[Pt(dien)]₂(dptmp)}(PF₆)₅ (1) and {[Pt(dpa)]₂(dptmp)}(PF₆)₅ (2), were synthesized, characterized and applied to a series of biochemical studies. FRET and SPR analyses showed these compounds, especially Pt(II) complexes, bound more strongly to human telomeric (hTel) G-quadruplex than to promoters (such as c-myc and bcl2) or to the duplex DNA. PCR-stop assays revealed that the Pt(II) complexes could bind to and stabilize G-quadruplex far more effectively than corresponding ligand. CD analyses further indicated the three compounds likely stabilized the formation of mixed-type parallel/antiparallel G-quadruplex structures. Their efficacy as telomerase inhibitors and potential anticancer drugs was explored via TRAP. The IC₅₀ value was determined to be 0.113 ± 0.019 μM for 1, indicating that it is one of the strongest known telomerase inhibitors. These results confirm that both V-shaped dinuclear Pt(II) complexes act as selective G-quadruplex binders and significant telomerase inhibitors.
一种季铵化的三嗪配体，4-[4,6-二（4-吡啶基）-1,3,5-（2-三嗪基）]-1-甲基吡啶-1-鎓六氟磷酸盐（dptmp·PF6），以及两个衍生的 V 型双核 Pt(II) 配合物，{[Pt(dien)]₂(dptmp)}(PF₆)₅（1）和{[Pt(dpa)]₂(dptmp)}(PF₆)₅（2），被合成、表征，并应用于一系列生化研究。FRET 和 SPR 分析表明，这些化合物，特别是 Pt(II) 配合物，与人类端粒（hTel）G-四链体的结合强度比启动子（如 c-myc 和 bcl2）或双链 DNA 更强。PCR 停止分析表明，Pt(II) 配合物能够更有效地结合并稳定 G-四链体，而不是相应的配体。CD 分析进一步表明，这三种化合物可能稳定形成混合型平行/反平行 G-四链体结构。通过 TRAP 探索了它们作为端粒酶抑制剂和潜在抗癌药物的功效。1 的 IC₅₀ 值为 0.113 ± 0.019 μM，表明其是已知最强的端粒酶抑制剂之一。这些结果证实，这两种 V 型双核 Pt(II) 配合物均作为选择性 G-四链体结合物和显著的端粒酶抑制剂起作用。
