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.

中文翻译：

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新型基于喹啉的Ir（III）配合物在体外和体内均表现出高抗肿瘤活性。

细胞毒性机理研究表明，八种Ir（III）配合物对癌细胞NCI-H460，T-24和HeLa有选择性地表现出高度有效的抗肿瘤活性，而对非癌细胞系HL-7702没有活性。在八种Ir（III）配合物中，MPytMP-Ir对NCI-H460细胞表现出最高的细胞毒性，IC50 = 5.05±0.22 nM。MPytMP-Ir的体外抗肿瘤活性可能与甲基的空间或电子作用有关，甲基可诱导端粒酶抑制和破坏NCI-H460细胞的线粒体。更重要的是，MPytMP-Ir对NCI-H460异种移植物的体内抑制作用优于顺铂。我们的工作表明，MPytMP-Ir可能被开发为新型有效的基于Ir的抗肿瘤药物。