IMDEA Nanociencia, Faraday 9, 28049 Madrid, Spain.
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K.
J Med Chem. 2020 Apr 23;63(8):4005-4021. doi: 10.1021/acs.jmedchem.9b02000. Epub 2020 Apr 1.
Six complexes of formula [Ir(η:κ-CMeCHpy)(C,N)]PF, where CMeCHpy is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (), 7,8-benzoquinoline (), 1-phenylisoquinoline (), 2-(-tolyl)pyridine (), 4-chloro-2-phenylquinoline (), or 2-(2,4-difluorophenyl)pyridine (), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η:κ-MeCHpy) tether-ring structure, as confirmed by the X-ray crystal structures of , , , , and . Nontether versions of and 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, -, are exceptionally more potent (1-2 orders of magnitude). Additionally, - disrupt mitochondrial membrane potential (ΔΨ) 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.
合成了[Ir(η:κ-CMeCHpy)(C,N)]PF 的六个配合物，其中 CMeCHpy 是 2-((2,3,4,5-四甲基环戊二烯基)甲基)吡啶，C,N 是 2-苯基吡啶 (), 7,8-苯并喹啉 (), 1-苯基异喹啉 (), 2-(-甲苯基)吡啶 (), 4-氯-2-苯基喹啉 (), 或 2-(2,4-二氟苯基)吡啶 ()。环戊二烯基配体带有一个连接到金属中心的桥连吡啶，导致 Ir(η:κ-MeCHpy)桥环结构，这通过 X 射线晶体结构得到证实，,,, 和. 为了明确结构与活性之间的关系，还合成了非桥连版本的 和. 虽然非桥连配合物对 MCF7 癌细胞具有很高的活性（类似于顺铂），但带有桥环结构的配合物, -, 则异常有效（1-2 个数量级）。此外，-还会破坏线粒体膜电位 (ΔΨ) 并诱导氧化应激。细胞内摄取研究强烈地将桥连和非桥连配合物的细胞内积累与抗癌活性相关联。我们提出了一类新的有机铱药物候选物，它们具有导致抗癌活性飞跃的结构特征。
