Six complexes of formula [Ir(η5:κ1-C5Me4CH2py)(C,N)]PF6, where C5Me4CH2py is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (1), 7,8-benzoquinoline (2), 1-phenylisoquinoline (3), 2-(p-tolyl)pyridine (4), 4-chloro-2-phenylquinoline (5), or 2-(2,4-difluorophenyl)pyridine (6), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η5:κ1-C5Me4CH2pyN) tether-ring structure, as confirmed by the X-ray crystal structures of 1, 2, 4, 5, and 6. Nontether versions of 1 and 2 were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, 1-6, are exceptionally more potent (1-2 orders of magnitude). Additionally, 1-6 disrupt mitochondrial membrane potential (ΔΨm) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.

中文翻译：

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结构上紧张的半夹心铱（III）络合物作为高效抗癌剂。

六种式[Ir（η5：κ1-C5Me4CH2py）（C，N）] PF6的配合物，其中C5Me4CH2py为2-（（2,3,4,5-四甲基环戊二烯基）甲基）吡啶，C，N为2-苯基吡啶（1），7,8-苯并喹啉（2），1-苯基异喹啉（3），2-（对甲苯基）吡啶（4），4-氯-2-苯基喹啉（5）或2-（2,4 -二氟苯基）吡啶（6）已经合成。环戊二烯基配体带有与金属中心结合的束缚吡啶，形成Ir（η5：κ1-C5Me4CH2pyN）束缚环结构，这一点已通过X，1、2、4、5和6的晶体结构证实合成了1和2的非系链版本，以帮助结构和活性之间的明确关联。虽然非系链复合物对MCF7癌细胞（与顺铂相似）具有很高的效力，但带有系链环结构1-6的复合物却具有更高的效力（1-2个数量级）。另外，1-6破坏线粒体膜电位（ΔΨm）并诱导氧化应激。内部化研究与系链和非系链复合物中的细胞内积累和抗癌活性密切相关。我们提出了具有结构特征的新型有机铱药物候选物，该结构特征导致了抗癌效力的飞跃。