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In this paper, three new Ruthenium(II) polypyridyl complexes containing ascididemin (ASC) as main ligand have been synthesized and characterized. Their interactions with different G-quadruplex (Htelo, c-myc and c-kit) (Htelo: human telomeric DNA, c-myc: cellular-myelocytomatosis viral oncogene, c-kit: oncogene c-kit promoter sequences) and duplex (ds26) DNA sequences were comparatively studied with the free ligand ASC by a series of spectroscopic techniques including UV–vis (ultraviolet-visible) spectroscopy, FID (fluorescent intercalator displacement) assay, and FRET (fluorescence resonance energy transfer) melting assay. Molecular docking studies were also performed to support the binding mode of the compounds with G-quadruplex DNA. Results indicated that [Ru(bpy) 2 ASC]·(PF 6) 2 (1), [Ru(phen) 2 ASC]·(PF 6) 2 (2), [Ru(tatp) 2 ASC]·(PF 6) 2 (3) (bpy = 2,2′‑bipyridine, phen = 1,10‑phenanthroline, tatp = 1,4,8,9‑tetra‑aza‑triphenylene) and ASC can effectively bind G-quadruplex and duplex DNA and stabilization ability lies in the order 3 > 2 > 1 > ASC. Complex 3 was determined to be the most promising candidate for further in vitro studies and potential anticancer drug. The act of conjugating ascididemin (ASC) ligands to a Ru(II) polypyridyl subunits resulted in a class of excellent DNA binders. Especially, [Ru(1,4,8,9‑tetra‑aza‑triphenylene) 2 ASC]·(PF 6) 2 (3) showed the strongest quadruplex and duplex DNA binding and stabilization ability. Complex 3 was proposed to be the promising telomerase inhibitors and potential anticancer drug. Unlabelled Image • Three novel Ru(II) polypyridyl complexes have been synthesized and characterized. • Complexes 1 – 3 and ascididemin (ASC) can effectively bind G-quadruplex and duplex DNA. • Notably, complex 3 exhibited the strongest DNA binding and stabilization ability. • Complex 3 was determined to be the most promising candidate for further in vitro studies. • Complex 3 is [Ru(1,4,8,9‑tetra‑aza‑triphenylene) 2 ASC]·(PF 6) 2. [ABSTRACT FROM AUTHOR]