Abstract
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.
Highlights
Telomeres are believed to play a vital role in genome integrity by protecting the genomic DNA from degradation and deleterious recombination events such as end-to-end fusion, rearrangements, chromosomal translocations, and chromosomal loss [1,2]
The Ru-N pyridine distances vary in the 2.051–2.084 Å ranges, which are consistent with the typical values observed for related RuII polypyridyl complexes [39,40]
It was worth noting that [(dmb)2Ru(obip)Ru(dmb)2]4+ showed a distinct preference for HeLa cells, HeLa cells were chosen as a cell model for further investigation of the mechanisms underlying the antiproliferative action of [(dmb)2Ru(obip)Ru(dmb)2]4+. Since this complex [(dmb)2Ru(obip)Ru(dmb)2]4+ is potential to be developed as a cancer therapy drug, it is essential to determine whether this inhibition of telomerase activity and proliferation of cancer cells will further induce apoptotic death
Summary
Telomeres are believed to play a vital role in genome integrity by protecting the genomic DNA from degradation and deleterious recombination events such as end-to-end fusion, rearrangements, chromosomal translocations, and chromosomal loss [1,2]. We reported a new dinuclear complex [(dmb)2Ru(obip)Ru(dmb)2]4+ (Figure 1D) with remarkable ability to recognize human telomere derived G-quadruplex and inhibit telomerase activity in human cervical cancer Hela cells.
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