MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China.
J Biol Inorg Chem. 2012 Jan;17(1):81-96. doi: 10.1007/s00775-011-0831-6. Epub 2011 Aug 21.
DNA topoisomerases (I and II) have been one of the excellent targets in anticancer drug development. Here two chiral ruthenium(II) anthraquinone complexes, Δ- and Λ-Ru(bpy)(2)(ipad), where bpy is 2,2'-bipyridine and ipad is 2-(anthracene-9,10-dione-2-yl)imidazo[4,5-f][1,10]phenanthroline, were synthesized and characterized. As expected, both of the Ru(II) complexes intercalate into DNA base pairs and possess an obviously greater affinity with DNA. Topoisomerase inhibition and DNA strand passage assay confirmed that the two complexes are efficient dual inhibitors of topoisomerases I and II by interference with the DNA religation. In MTT cytotoxicity studies, two Ru(II) complexes exhibited antitumor activity against HeLa, MCF-7, HepG2 and BEL-7402 tumor cell lines. Flow cytometry analysis shows an increase in the percentage of cells with apoptotic morphological features in the sub-G1 phase for Ru(II) complexes. Nuclear chromatin cleavage has also been observed from AO/EB staining assay and alkaline single-cell gel electrophoresis (comet assay). The results demonstrated that Δ- and Λ-Ru(bpy)(2)(ipad) act as dual inhibitors of topoisomerases I and II, and cause DNA damage that can lead to cell cycle arrest and/or cell death by apoptosis.
DNA 拓扑异构酶（I 和 II）一直是抗癌药物开发的优秀靶点之一。这里合成并表征了两种手性钌（II）蒽醌配合物，Δ-和 Λ-Ru(bpy)(2)(ipad)，其中 bpy 是 2,2'-联吡啶，ipad 是 2-(蒽醌-9,10-二酮-2-基)咪唑[4,5-f][1,10]菲咯啉。正如预期的那样，两种 Ru(II) 配合物都嵌入 DNA 碱基对中，并且与 DNA 具有明显更大的亲和力。拓扑异构酶抑制和 DNA 链通过测定证实，两种配合物通过干扰 DNA 连接而有效地成为拓扑异构酶 I 和 II 的双重抑制剂。在 MTT 细胞毒性研究中，两种 Ru(II) 配合物对 HeLa、MCF-7、HepG2 和 BEL-7402 肿瘤细胞系表现出抗肿瘤活性。流式细胞术分析显示，Ru(II) 配合物使亚 G1 期具有凋亡形态特征的细胞百分比增加。吖啶橙/溴化乙锭（AO/EB）染色测定和碱性单细胞凝胶电泳（彗星试验）也观察到核染色质裂解。结果表明，Δ-和 Λ-Ru(bpy)(2)(ipad) 作为拓扑异构酶 I 和 II 的双重抑制剂，引起 DNA 损伤，可导致细胞周期停滞和/或细胞凋亡。
