Topoisomerase IIα poisoning and DNA double-stand breaking by chiral ruthenium(II) complexes containing 2-furanyl-imidazo[4,5-f][1,10]phenanthroline derivatives
Chen Qian, Jingheng Wu, Liangnian Ji, Hui Chao
Four chiral Ru(II) complexes bearing furan ligands, Delta/Lamda-[Ru(bpy)2(pocl)]2+(Delta/Lamda-1) and Delta/Lamda-[Ru(bpy)2(poi)]2+ (Delta/Lamda-2) (bpy = 2,2’-bipyridine, pocl = 2-(5-chlorofuran-2-yl)imidazo[4,5-f][1,10]phenanthroline, poi = 2-(5-5-iodofuran-2-yl)imidazo[4,5-f][1,10]phenanthroline), were synthesized and characterized. These Ru(II) complexes showed antitumor activities against HeLa, A549, HepG2, HL-60 and K562 tumor cell lines, especially HL-60 tumor cell line. Moreover, Delta-2 was more active than others complexes accounting for the different cellular uptake. In addition, Delta-2 could accumulate in the nucleus of HL-60 cells, suggesting that nucleic acids were the cellular target of Delta-2. Topoisomerase inhibition test in vitro and in living cells confirmed that four complexes acted as efficient topoisomerases IIα poison, DNA double-strand breaks had also been observed from neutral single cell gel electrophoresis (comet assay). Delta-2 inhibited the growth of HL-60 cells through the induction of apoptotic cell death, as evidenced by the Alexa Fluor® 488 annexin V staining assays. The results demonstrated that Delta-2 acted as topoisomerases IIα poison and caused DNA double-stand damage that could lead to apoptosis.
Circular dichroism, Stereochemistry, Inorganic chemistry, Biochemistry