Effect of ancillary ligands on the topoisomerases II and transcription inhibition activity of polypyridyl ruthenium(II) complexes.
Effect of ancillary ligands on the topoisomerases II and transcription inhibition activity of polypyridyl ruthenium(II) complexes.
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DOI：
10.1016/j.jinorgbio.2010.01.010
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发表时间：
2010-05
影响因子：
3.9
通讯作者：
Xing-Xiu Chen;Feng Gao;Zhuohua Zhou;Wei-Yan Yang;Li-Tian Guo;L. Ji
中科院分区：
文献类型：
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作者：
Xing-Xiu Chen;Feng Gao;Zhuohua Zhou;Wei-Yan Yang;Li-Tian Guo;L. Ji
为了探索多吡啶Ru(II)配合物作为拓扑异构酶II和T7RNA聚合酶抑制剂的构效关系，合成了四个新的配合物：[Ru(4dmb)2(ppd)]2+(4dmb=4，4′-dimethyl-2，2′-bipyridine，ppd=蝶呤并[6，7-f][1，10]邻菲咯啉-1，13(10H，12H)-二酮)，[Ru(5dmb)2(ppd)]2+(5dmb=5，5′-dimethyl-2，2′-bipyridine)，[Ru(dip)2(ppd)]2+(dip=4，7-diphenyl-1，10-phenanthroline)，合成了[Ru(ip)2(ppd)]2+(ip=imidazole[4，5-f][1，10]phenanthroline)，并用核磁共振氢谱、质谱学和元素分析对其进行了详细的表征。研究了它们与小牛胸腺DNA的相互作用以及对拓扑异构酶II和T7RNA聚合酶的抑制活性。结果表明，虽然这四种Ru(II)配合物都是有效的DNA嵌入剂、拓扑异构酶II抑制剂和DNA转录抑制剂，但它们与DNA的结合强度和抑制活性有很大的不同。IP-和DIP-络合物的活性明显高于DMB-络合物。为了解释实验规律，揭示生物活性的内在量子化学机制，用密度泛函理论(DFT)和含时密度泛函理论(TDDFT)计算了这些化合物的前线分子轨道的能级、布居和激发态跃迁的性质。结果表明，辅助配体具有较低的最低空轨道能量(Lumos)、较好的疏水性和较小的空间位阻，有利于DNA的嵌入和拓扑异构酶II和DNA转录的抑制。
To explore the structure-activity relationship of polypyridyl ruthenium(II) complexes as topoisomerase II and T7 RNA polymerase inhibitors, four new complexes, [Ru(4dmb)2(ppd)]2+(4dmb=4,4′-dimethyl-2,2′-bipyridine, ppd=pteridino[6,7-f][1,10] phenanthroline-1,13(10H,12H)-dione), [Ru(5dmb)2(ppd)]2+(5dmb=5,5′-dimethyl-2,2′-bipyridine), [Ru(dip)2(ppd)]2+(dip=4,7-diphenyl-1,10-phenanthroline), and [Ru(ip)2(ppd)]2+(ip=imidazole[4,5-f][1,10]phenanthroline) have been synthesized and characterized in detail by1H NMR spectroscopy, mass spectrometry and elemental analysis. Their interaction with calf thymus DNA and the inhibitory activity towards topoisomerase II and T7 RNA polymerase were investigated. The results suggest that although all of these four Ru(II) complexes are potent DNA intercalators, topoisomerase II inhibitors and DNA transcription inhibitors, their DNA binding strength and inhibitory activities are quite different. The activity of ip- and dip-complexes are significantly higher than the dmb-complexes. To explain the experimental regularity and reveal the underlying quantum chemistry mechanism of the biological activity, the properties of energy levels and population of frontier molecular orbitals and excited state transitions of these complexes have been studied by density functional theory (DFT) and time-depended DFT (TDDFT) calculations. The results suggest that ancillary ligands bearing lower energy of the lowest unoccupied molecular orbitals (LUMOs), better hydrophobicity and less steric hindrance of are beneficial to the DNA intercalation and topoisomerase II and DNA transcription inhibition of their complexes.