Gao Feng, Chao Hui, Wang Jin-Quan, Yuan Yi-Xian, Sun Bin, Wei Yuan-Fang, Peng Bin, Ji Liang-Nian
Key Laboratory of Bioinorganic and Synthetic Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China.
J Biol Inorg Chem. 2007 Sep;12(7):1015-27. doi: 10.1007/s00775-007-0272-4. Epub 2007 Jul 21.
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 Delta--Ru(bpy)(2)(uip) and Lambda-Ru(bpy)(2)(uip) (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 ((1)O(2)) and superoxide anion radical (O (2) (*-) ) 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.
许多抗肿瘤药物作为拓扑异构酶抑制剂发挥作用，且这些抑制作用通常与DNA结合有关。在此，我们设计并合成了DNA插入型钌（II）多吡啶配合物Δ-[Ru(bpy)₂(uip)]²⁺和Λ-[Ru(bpy)₂(uip)]²⁺（bpy为2,2'-联吡啶，uip为2-(5-尿嘧啶)-1H-咪唑并[4,5-f][1,10]菲咯啉）。研究了这些配合物的DNA结合、光裂解、拓扑异构酶抑制及细胞毒性。正如我们所预期的，合成的钌（II）配合物能够插入DNA碱基对，并在光照下以高活性裂解pBR322 DNA。机制研究表明，单线态氧（¹O₂）和超氧阴离子自由基（O₂⁻*）可能在光裂解过程中起重要作用。已研究了钌（II）配合物对拓扑异构酶I和II的抑制作用。结果表明，这两种配合物都是通过干扰DNA再连接和直接与拓扑异构酶II结合而成为拓扑异构酶II的有效抑制剂。两种配合物对HELA、hepG2、BEL-7402和CNE-1肿瘤细胞均显示出抗肿瘤活性。
