Cytotoxicity of Pyrazine-Based Cyclometalated (C^N(pz)^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties.
Cytotoxicity of Pyrazine-Based Cyclometalated (C^N(pz)^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties.
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DOI：
10.1021/acs.inorgchem.7b00339
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发表时间：
2017-05-15
影响因子：
4.6
通讯作者：
Bochmann M
中科院分区：
文献类型：
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作者：
Bertrand B;Fernandez-Cestau J;Angulo J;Cominetti MMD;Waller ZAE;Searcey M;O'Connell MA;Bochmann M
报道了一系列吡嗪类（C^N^C）钳形配体负载的环化金（III）配合物的合成，包括阳离子实例的晶体结构。这些化合物为研究金（III）配合物的抗增殖特性提供了新的平台。测试了七种复合物：中性系列（C^Npz^C）AuX [X = Cl（1），6-硫代鸟嘌呤（4），C ^CPh（5），SPh（6）]和离子系列，包括N-甲基络合物[（C^Npz ^C）AuCl] BF 4（7）和N-杂环卡宾络合物[（C^Npz^C）AuL]+，其中L = 1，3-二甲基苯并咪唑-2-亚基（2）或1，3，7，9-四甲基黄嘌呤-8-亚基（3）。针对人类白血病细胞的测试发现1、2、3和4特别有希望，而通过甲基化保护吡嗪环上的非配位N原子（如7）降低了细胞毒性。复合物2被证明是针对HL 60白血病、MCF-7乳腺癌和A549肺癌细胞系的整个系列中最有效的，IC 50值低至亚微摩尔水平，与对健康人肺成纤维细胞的较低毒性相关。苯并咪唑亚基络合物2在人肺癌细胞中的积累比其基于咖啡因的类似物3和氯化金（III）1更有效。化合物2被证明在生理条件下不受谷胱甘肽的影响长达6天，并稳定DNA G-四链体和i-基序结构;后者是金化合物的第一个此类报告。我们还显示了抑制MDM 2-p53蛋白质-蛋白质相互作用的金基化合物的第一个证据，并确定了该化合物与MDM 2的结合模式，使用饱和转移差NMR光谱结合对接计算。我们合成了三个新的（C^Npz^C）Au（III）配合物，并与其他四个配合物一起进行了沿着。我们测试了细胞摄取、与G4和i-motif DNA结构的相互作用以及与MDM 2蛋白的相互作用。我们强调了由于不同的辅助配体，化合物的生物学行为非常不同。
The synthesis of a series of cyclometalated gold(III) complexes supported by pyrazine-based (C^N^C)-type pincer ligands is reported, including the crystal structure of a cationic example. The compounds provide a new platform for the study of antiproliferative properties of gold(III) complexes. Seven complexes were tested: the neutral series (C^Npz^C)AuX [X = Cl (1), 6-thioguanine (4), C≡CPh (5), SPh (6)] and an ionic series that included the N-methyl complex [(C^NpzMe^C)AuCl]BF4 (7) and the N-heterocyclic carbene complexes [(C^Npz^C)AuL]+ with L = 1,3-dimethylbenzimidazol-2-ylidene (2) or 1,3,7,9-tetramethylxanthin-8-ylidene (3). Tests against human leukemia cells identified 1, 2, 3, and 4 as particularly promising, whereas protecting the noncoordinated N atom on the pyrazine ring by methylation (as in 7) reduced the cytotoxicity. Complex 2 proved to be the most effective of the entire series against the HL60 leukemia, MCF-7 breast cancer, and A549 lung cancer cell lines, with IC50 values down to submicromolar levels, associated with a lower toxicity toward healthy human lung fibroblast cells. The benzimidazolylidene complex 2 accumulated more effectively in human lung cancer cells than its caffeine-based analogue 3 and the gold(III) chloride 1. Compound 2 proved to be unaffected by glutathione under physiological conditions for periods of up to 6 days and stabilizes the DNA G-quadruplex and i-motif structures; the latter is the first such report for gold compounds. We also show the first evidence of inhibition of MDM2–p53 protein–protein interactions by a gold-based compound and identified the binding mode of the compound with MDM2 using saturation transfer difference NMR spectroscopy combined with docking calculations. We synthesized three new (C^Npz^C)Au(III) complexes and screened them along with four other complexes as potential anticancer agents against leukemia cells. We tested the cellular uptake, the interaction with G4 and i-motif DNA structures, and the interaction with MDM2 protein. We highlight the very different biological behaviors of the compounds due to the different ancillary ligands.