Targeting topoisomerase II with the chiral DNA-intercalating ruthenium(II) polypyridyl complexes.
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)](2+) and Lambda-[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 ((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.
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
F
Gao
Hui
H
Chao
Jin-Quan
JQ
Wang
Yi-Xian
YX
Yuan
Bin
B
Sun
Yuan-Fang
YF
Wei
Bin
B
Peng
Liang-Nian
LN
Ji
D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics; D059005:Topoisomerase II Inhibitors
D007364:Intercalating Agents; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D012428:Ruthenium; D004247:DNA