Live Cell Cytotoxicity Studies: Documentation of the Interactions of Antitumor Active Dirhodium Compounds with Nuclear DNA
Live Cell Cytotoxicity Studies: Documentation of the Interactions of Antitumor Active Dirhodium Compounds with Nuclear DNA
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DOI：
10.1021/ja9021717
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发表时间：
2009-08-19
影响因子：
15
通讯作者：
Dunbar, Kim R.
中科院分区：
文献类型：
--
作者：
Aguirre, J. Dafhne;Angeles-Boza, Alfredo M.;Dunbar, Kim R.
地铑配合物具有良好的抗肿瘤活性已有30多年的历史。然而，仍然普遍缺乏对它们在细胞中的活性的了解。本文报道了六种单取代二铑（Ⅱ，Ⅱ）配合物[Rh-2]与DNA的相互作用及其在活细胞中的活性（μ-O2CCH3）（2）（eta '-O2 CCH 3）（L）（CH 3OH）]（+），其中L = bpy（2，2'-bipyridine）（1），phen（1，10-菲咯啉）（2），dpq（双吡啶并[3，2-f：2 ′，3 ′-h]喹喔啉）（3）、DPPZ（双吡啶并[3，2-a：2 ′，3 ′-c]吩嗪）（4）、DPPN（苯并[i]双吡啶并[3，2-a：2 ′，3 ′-c]吩嗪）（5）和DAP（4，7-二氢二苯并[de，gh][1，10]菲咯啉）（6）。DNA相互作用进行了研究，通过紫外/可见光谱，相对粘度测量，和电泳迁移率变动分析。这些测量表明化合物5表现出与DNA的最强相互作用。如通过碱性彗星测定所评估的，化合物5还在细胞内化后引起对DNA的最大损伤。然而，化合物5在抑制人癌细胞HeLa和科洛-316的细胞活力方面不是最有效的。5的疏水性比4的疏水性更大，4是该系列中最有效的化合物，这阻碍了其到达其细胞靶标的能力。使用N-乙酰半胱氨酸和L-丁硫氨酸-亚砜亚胺的谷胱甘肽调制研究的数据表明，谷胱甘肽水平的变化不影响活性。这些特殊的二铑络合物。这些结果表明，谷胱甘肽是不是唯一的代理参与这些dirhodium络合物的失活。
The promising antitumor activity of dirhodium complexes has been known for over 30 years. there remains, however, a general lack of understanding of their activity in cellulo. In this study, we report the DNA interactions and activity in living cells of six monosubstituted dirhodium(II,II) complexes of general formula [Rh-2(mu-O2CCH3)(2)(eta'-O2CCH3)(L)(CH3OH)](+), where L = bpy (2,2'-bipyridine) (1), phen (1,10-phenanthroline) (2), dpq (dipyrido[3,2-f:2',3'-h)quinoxaline) (3), dppz (dipyrido[3,2-a:2',3'-c]phenazine) (4), dppn (benzo[i]dipyrido[3,2-a:2',3'-c]phenazine) (5), and dap, (4,7-dihydrodibenzo[de,gh][1,10]phenanthroline) (6). DNA interactions were investigated by UV/visible spectroscopy, relative viscosity measurements, and electrophoretic mobility shift assay. These measurements indicate that compound 5 exhibits the strongest interaction with DNA. Compound 5 also causes the most damage to DNA after cellular internalization, as evaluated by the alkaline comet assay. Compound 5, however, is not the most effective at inhibiting cell viability of the human cancer cells HeLa and COLO-316. The greater hydrophobicity of 5 as compared to that of 4, which is the most effective compound in the series, hinders its ability to reach its cellular target(s). Data from modulation studies of glutathione using N-acetylcysteine and L-buthionine-sulfoximine indicate that changes in glutathione levels do not affect the activity. of these particular dirhodium complexes. These results suggest that glutathione is not the only agent involved in the deactivation of these dirhodium complexes.