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

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Abstract

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 (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.

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Acknowledgements

We are grateful to the support of the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, the Research Fund for the Doctoral Program of Higher Education, the Program for New Century Excellent Talents in University, the Scientific Research Foundation for the Returned Overseas Chinese Scholars of the Ministry of Education, and the State Key Laboratory of Coordination Chemistry in Nanjing University.

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Authors and Affiliations

  1. 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

    Feng Gao, Hui Chao, Yi-Xian Yuan, Bin Sun, Yuan-Fang Wei, Bin Peng & Liang-Nian Ji

  2. State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, 210093, People’s Republic of China

    Hui Chao

  3. School of Life Science and Biopharmacology, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Jin-Quan Wang

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  1. Feng Gao
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Correspondence to Hui Chao or Liang-Nian Ji.

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Gao, F., Chao, H., Wang, JQ. et al. Targeting topoisomerase II with the chiral DNA-intercalating ruthenium(II) polypyridyl complexes. J Biol Inorg Chem 12, 1015–1027 (2007). https://doi.org/10.1007/s00775-007-0272-4

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