Targeting Human Telomeric G-Quadruplex DNA and Inhibition of Telomerase Activity With [(dmb)(2)Ru(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)(2)Ru(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)(2)Ru(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)(2)Ru(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, Ru(II) complex represents an exciting opportunity for anticancer drug design by specifically targeting cancer cell G-quadruplexes DNA.