Department of Chemistry, McGill University, Montreal, QC, Canada.
ChemMedChem. 2012 Jan 2;7(1):85-94. doi: 10.1002/cmdc.201100453. Epub 2011 Nov 3.
A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere-derived intramolecular G-quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G-quadruplexes from sequences based on the human telomeric repeat (TTAGGG)(n). The greatest stabilization was observed for the p-chlorophenyl derivative 6((G4)DC(50) =0.31 μM). We also show that the G-quadruplex binding complexes are able to inhibit telomerase activity through a modified telomerase repeat amplification protocol (TRAP-LIG assay). Preliminary cell studies show that complex 6 is preferentially cytotoxic toward cancer over normal cell lines, indicating its potential use in cancer therapy.
我们研究了一系列经过合理设计的菲并咪唑铂(II)配合物，以考察它们靶向端粒衍生的分子内 G-四链体 DNA 的能力。通过使用圆二色性、荧光置换分析和分子建模，我们表明这些配合物可以模板化并稳定基于人端粒重复序列 (TTAGGG)(n) 的 G-四链体。观察到最大稳定化的是对氯苯基衍生物 6((G4)DC(50)=0.31 μM)。我们还表明，G-四链体结合配合物能够通过改良的端粒酶重复扩增协议 (TRAP-LIG 测定) 抑制端粒酶活性。初步的细胞研究表明，配合物 6 对癌细胞的细胞毒性优于正常细胞系，表明其在癌症治疗中的潜在用途。
