Targeting Human Telomeric G-Quadruplex DNA and Inhibition of Telomerase Activity With [(dmb)2Ru(obip)Ru(dmb)2]4+

Inhibition of telomerase by inducing/stabilizing G-quadruplex formation is a promising strategy to design new anticancer drugs. We synthesized and characterized a new dinuclear complex [(dmb)2Ru(obip)Ru(dmb)2]4+ (dmb = 4,4’-dimethyl-2,2’-bipyridine, obip = (2-(2-pyridyl)imidazo[4,5-f][1,10]phenanthroline) with high affinity for both antiparallel and mixed parallel / antiparallel G-quadruplex DNA. This complex can promote the formation and stabilize G-quadruplex DNA. Dialysis and TRAP experiments indicated that [(dmb)2Ru(obip)Ru(dmb)2]4+ acted as an excellent telomerase inhibitor due to its obvious selectivity for G-quadruplex DNA rather than double stranded DNA. In vitro co-culture experiments implied that [(dmb)2Ru(obip)Ru(dmb)2]4+ inhibited telomerase activity and hindered cancer cell proliferation without side effects to normal fibroblast cells. TUNEL assay indicated that inhibition of telomerase activity induced DNA cleavage further apoptosis in cancer cells. Therefore, RuII complex represents an exciting opportunity for anticancer drug design by specifically targeting cancer cell G-quadruplexes DNA.

通过诱导/稳定G-四链体（G-quadruplex）形成来抑制端粒酶，是设计新型抗癌药物的极具前景的策略。我们合成并表征了一种新型双核配合物[(dmb)₂Ru(obip)Ru(dmb)₂]⁴⁺（其中dmb=4,4’-二甲基-2,2’-联吡啶，obip=(2-(2-吡啶基)咪唑并[4,5-f][1,10]邻菲啰啉)），该配合物对反平行及混合平行/反平行G-四链体DNA均具有较高结合亲和力。该配合物可促进G-四链体DNA的形成并对其起到稳定作用。透析实验与TRAP实验结果表明，[(dmb)₂Ru(obip)Ru(dmb)₂]⁴⁺对G-四链体DNA相较于双链DNA具有显著选择性，因此是一类优异的端粒酶抑制剂。体外共培养实验显示，[(dmb)₂Ru(obip)Ru(dmb)₂]⁴⁺可抑制端粒酶活性、阻碍癌细胞增殖，且对正常成纤维细胞无副作用。TUNEL测定结果表明，端粒酶活性的抑制会诱导DNA断裂，进而引发癌细胞凋亡。因此，该钌(II)配合物通过特异性靶向癌细胞G-四链体DNA，为抗癌药物的开发提供了极具潜力的新思路。