High in Vitro and in Vivo Tumor-Selective Novel Ruthenium(II) Complexes with 3‑(2′-Benzimidazolyl)-7-fluoro-coumarin

Three novel Ru­(II) complexes, namely, (RuCl2[La]­[DMSO]2)·H2O (Ru1), (RuCl2[Lb]­[DMSO]2) (Ru2), and (RuCl2[Lc]­[DMSO]2) (Ru3), which respectively contain 3-(2′-benzimidazolyl)­coumarin (La), 3-(2′-benzimidazolyl)-7-fluoro-coumarin (Lb), and 3-(2′-benzimidazolyl)-7-methoxyl-coumarin (Lc), were first designed and characterized. Ru2 showed potent antitumor activity against NCI-H460 cells (IC50 = 0.30 ± 0.02 μM) and high selectivity between NCI-H460 cancer cells and normal HL-7702 cells. Ru2 induced NCI-H460 apoptosis via telomerase inhibition, which involved DNA damage, cell-cycle distribution, and S phase-protein down-regulation. However, Ru1 did not demonstrate such effects in NCI-H460 cells, which is undoubtedly associated with the key regulatory role of the 7-fluoro substituted group in the Lb ligand of Ru2. Ru2 exhibited considerably higher anticancer efficacy (inhibition rate [IR] = 61.3%) compared with cisplatin (IR= 25.5%) in a NCI-H460 xenograft mouse model. Thus, this coumarin Ru­(II) compound is a promising Ru2-targeting telomerase anticancer agent.