Department of Chemistry, University of Warwick, UK.
Metallomics. 2018 Jan 24;10(1):93-107. doi: 10.1039/c7mt00242d.
Resistance to platinum drugs (used in >50% of cancer chemotherapies) is a clinical problem. Other precious metal complexes with distinct mechanisms of action might overcome this. Half-sandwich organometallic complexes containing arene or cyclopentadienyl (Cp) ligands show promise. We screened two iridium(iii) complexes [Ir(Cp)(ppy)Cl] (ZL49, 1, ppy = phenylpyridine) and [Ir(Cp)(azpyNMe)Cl]PF (ZL109, 2, azpyNMe = N,N-dimethylphenylazopyridine) in 916 cancer cell lines from 28 tissue types. On average, complex 2 was 78× more potent than 1, 36× more active than cisplatin (CDDP), and strongly active (nanomolar) in patient-derived ovarian cancer cell lines. RNA sequencing of A2780 ovarian cells revealed upregulation of antioxidant responses (NRF2, AP-1) consistent with observed induction of reactive oxygen species (ROS). Protein microarrays, high content imaging and cell cycle analysis showed S/G2 arrest, and late-stage DNA damage response without p53 requirement. The triple-negative breast cancer cell line OCUB-M was highly sensitive to 2 as were cell lines with KIT mutations. Complex 2 exhibits a markedly different pattern of antiproliferative activity compared to the 253 drugs in the Sanger Cancer Genome database, but is most similar to osmium(ii) arene complexes which share the same azopyridine ligand. Redox modulation and DNA damage can provide a multi-targeting strategy, allowing compounds such as 2 to overcome cellular resistance to platinum anticancer drugs.
对铂类药物（用于超过 50%的癌症化疗药物）的耐药性是一个临床问题。具有不同作用机制的其他贵金属配合物可能克服这一问题。含有芳烃或环戊二烯基（Cp）配体的半夹心有机金属配合物显示出前景。我们在 28 种组织类型的 916 种癌细胞系中筛选了两种铱（III）配合物[Ir（Cp）（ppy）Cl]（ZL49，1，ppy = 苯基吡啶）和[Ir（Cp）（azpyNMe）Cl]PF（ZL109，2，azpyNMe = N，N-二甲基苯基偶氮吡啶）。平均而言，配合物 2 比 1 强 78 倍，比顺铂（CDDP）强 36 倍，在源自患者的卵巢癌细胞系中活性很强（纳摩尔级）。A2780 卵巢细胞的 RNA 测序显示抗氧化反应（NRF2，AP-1）上调，与观察到的活性氧（ROS）诱导一致。蛋白质微阵列、高内涵成像和细胞周期分析显示 S/G2 期停滞和晚期 DNA 损伤反应，而无需 p53 要求。三阴性乳腺癌细胞系 OCUB-M 对 2 非常敏感，而 KIT 突变的细胞系也是如此。与 Sanger 癌症基因组数据库中的 253 种药物相比，配合物 2 表现出明显不同的抗增殖活性模式，但与共享相同偶氮吡啶配体的锇（II）芳烃配合物最为相似。氧化还原调节和 DNA 损伤可以提供一种多靶点策略，使配合物（如 2）能够克服细胞对铂类抗癌药物的耐药性。
