Novel Quinoline-based Ir(III) Complexes Exhibit High Antitumor Activity in Vitro and in Vivo

Eight novel Ir(III) complexes listed as [Ir(H-P)₂(P)]PF₆ (PyP-Ir), [Ir(H-P)₂(dMP)]PF₆ (PydMP-Ir), [Ir(H-P)₂(MP)]PF₆ (PyMP-Ir), [Ir(H-P)₂(tMP)]PF₆ (PytMP-Ir), [Ir(MPy)₂(P)]PF₆ (MPyP-Ir), [Ir(MPy)₂(dMP)]PF₆ (MPydMP-Ir), [Ir(MPy)₂(MP)]PF₆ (MPyMP-Ir), [Ir(MPy)₂((tMP)]PF₆ (MPytMP-Ir) with 2-phenylpyri-dine (H-P) and 3-methyl-2-phenylpyridine (MPy) as ancillary ligands and pyrido-[3,2-a]-pyrido[1',2':1,2]imidazo[4,5-c]phenazine (P), 12,13-dimethyl pyrido-[3,2-a]-pyrido[1',2':1,2]-imidazo-[4,5-c]-phenazine (dMP), 2-methylpyrido [3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1',2':1,2]-imidazo-[4,5-c]-phenazine (tMP) as main ligands, respectively, were designed and synthesized to fully characterize and explore the effect of their toxicity on cancer cells. Cytotoxic mechanism studies demonstrated that the eight Ir(III) complexes exhibited highly potent antitumor activity selectively against cancer cell lines NCI-H460, T-24, and HeLa, and no activity against HL-7702, a noncancerous cell line. Among the eight Ir(III) complexes, MPytMP-Ir exhibited the highest cytotoxicity with an IC₅₀ = 5.05 ± 0.22 nM against NCI-H460 cells. The antitumor activity of MPytMP-Ir in vitro could be contributed to the steric or electronic effect of the methyl groups, which induced telomerase inhibition and damaged mitochondria in NCI-H460 cells. More importantly, MPytMP-Ir displayed a superior inhibitory effect on NCI-H460 xenograft in vivo than cisplatin. Our work demonstrates that MPytMP-Ir could potentially be developed as a novel potent Ir-based antitumor drug.