Targeting Human Telomeric G-Quadruplex DNA and Inhibition of Telomerase Activity With [(dmb)2Ru(obip)Ru(dmb)2]4+
نویسندگان
چکیده
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, Ru(II) complex represents an exciting opportunity for anticancer drug design by specifically targeting cancer cell G-quadruplexes DNA.
منابع مشابه
Identification of G-Quadruplex Inducers Usinga Simple, Inexpensiveand Rapid High Throughput Assay, and TheirInhibition of Human Telomerase
Telomeres are protein and DNA complexes located atchromosome ends. Telomeric DNA is composed of a double stranded region of repetitive DNA followed by single-stranded 3' extension of aG-rich sequence. Single-stranded G-rich sequencescan fold into G-quadruplex structures,and molecules that stabilize G-quadruplexes are known to inhibit the enzyme telomerase and disrupt telomere maintenance. Becau...
متن کاملChiral Ruthenium(II) Polypyridyl Complexes: Stabilization of G-Quadruplex DNA, Inhibition of Telomerase Activity and Cellular Uptake
Two ruthenium(II) complexes, Λ-[Ru(phen)(2)(p-HPIP)](2+) and Δ-[Ru(phen)(2)(p-HPIP)](2+), were synthesized and characterized via proton nuclear magnetic resonance spectroscopy, electrospray ionization-mass spectrometry, and circular dichroism spectroscopy. This study aims to clarify the anticancer effect of metal complexes as novel and potent telomerase inhibitors and cellular nucleus target dr...
متن کاملSpecific binding of telomeric G-quadruplexes by hydrosoluble perylene derivatives inhibits repeat addition processivity of human telomerase.
Telomerase is responsible for the immortal phenotype of cancer cells and telomerase inhibition may specifically target cancer cell proliferation. Ligands able to selectively bind to G-quadruplex telomeric DNA have been considered as telomerase inhibitors but their mechanisms of action have often been deduced from a non-quantitative telomerase activity assay (TRAP assay) that involves a PCR step...
متن کاملHuman telomeric DNA forms parallel-stranded intramolecular G-quadruplex in K+ solution under molecular crowding condition.
The G-rich strand of human telomeric DNA can fold into a four-stranded structure called G-quadruplex and inhibit telomerase activity that is expressed in 85-90% tumor cells. For this reason, telomere quadruplex is emerging as a potential therapeutic target for cancer. Information on the structure of the quadruplex in the physiological environment is important for structure-based drug design tar...
متن کاملTelomere targeting with a novel G-quadruplex-interactive ligand BRACO-19 induces T-loop disassembly and telomerase displacement in human glioblastoma cells
Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA 3'-overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends, making these ligands good candidates for chemotherapeutic purposes. BRACO-19 is one of the most effe...
متن کامل