Targeting topoisomerase II with the chiral DNA-intercalating ruthenium(II) polypyridyl complexes

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• 作者：Feng Gao ; Hui Chao ; Jin-Quan Wang ; Yi-Xian Yuan ; Bin Sun ; Yuan-Fang Wei ; Bin Peng and Liang-Nian Ji
• 关键词：Ruthenium(II) complexes ; DNA binding ; Photocleavage ; Topoisomerase inhibition ; Cytotoxicity
• 刊名：Journal of Biological Inorganic Chemistry
• 出版年：2007
• 出版时间：September, 2007
• 年：2007
• 卷：12
• 期：7
• 页码：1015-1027
• 全文大小：681 KB

文摘

Many antitumor drugs act as topoisomerase inhibitors, and the inhibitions are usually related to DNA binding. Here we designed and synthesized DNA-intercalating Ru(II) polypyridyl complexes Δ--[Ru(bpy)₂(uip)]2+ and Λ-[Ru(bpy)₂(uip)]2+ (bpy is 2,2′-bipyridyl, uip is 2-(5-uracil)-1H-imidazo[4,5-f][1,10]phenanthroline). The DNA binding, photocleavage, topoisomerase inhibition, and cytotoxicity of the complexes were studied. As we expected, the synthesized Ru(II) complexes can intercalate into DNA base pairs and cleave the pBR322 DNA with high activity upon irradiation. The mechanism studies reveal that singlet oxygen (1O₂) and superoxide anion radical (O₂•−) may play an important role in the photocleavage. The inhibition of topoisomerases I and II by the Ru(II) complexes has been studied. The results suggest that both complexes are efficient inhibitors towards topoisomerase II by interference with the DNA religation and direct topoisomerase II binding. Both complexes show antitumor activity towards HELA, hepG2, BEL-7402, and CNE-1 tumor cells.