单功能钌（II）芳烃配合物修饰的DNA构象：DNA结合蛋白的识别与修复。与细胞毒性的关系。

Conformation of DNA modified by monofunctional Ru(II) arene complexes: recognition by DNA binding proteins and repair. Relationship to cytotoxicity.

作者信息

Novakova Olga, Kasparkova Jana, Bursova Vendula, Hofr Ctirad, Vojtiskova Marie, Chen Haimei, Sadler Peter J, Brabec Viktor

机构信息

Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.

出版信息

Chem Biol. 2005 Jan;12(1):121-9. doi: 10.1016/j.chembiol.2004.11.008.

DOI:10.1016/j.chembiol.2004.11.008

PMID:15664521

Abstract

We analyzed DNA duplexes modified at central guanine residues by monofunctional Ru(II) arene complexes (eta(6)-arene)Ru(II)(en)(Cl) (arene = tetrahydroanthracene or p-cymene, Ru-THA or Ru-CYM, respectively). These two complexes were chosen as representatives of two different classes of Ru(II) arene compounds for which initial studies revealed different binding modes: one that may involve DNA intercalation (tricyclic-ring Ru-THA) and the other (mono-ring Ru-CYM) that may not. Ru-THA is approximately 20 times more toxic to cancer cells than Ru-CYM. The adducts of Ru-THA and Ru-CYM have contrasting effects on the conformation, thermodynamic stability, and polymerization of DNA in vitro. In addition, the adducts of Ru-CYM are removed from DNA more efficiently than those of Ru-THA. Interestingly, the mammalian nucleotide excision repair system has low efficiency for excision of ruthenium adducts compared to cisplatin intrastrand crosslinks.

摘要

我们分析了由单功能钌（II）芳烃配合物[(η(6)-芳烃)Ru(II)(en)(Cl)]⁺（芳烃分别为四氢蒽或对异丙基苯，即Ru-THA或Ru-CYM）修饰中心鸟嘌呤残基的DNA双链体。选择这两种配合物作为两类不同钌（II）芳烃化合物的代表，初步研究表明它们具有不同的结合模式：一种可能涉及DNA插入（三环Ru-THA），另一种（单环Ru-CYM）可能不涉及。Ru-THA对癌细胞的毒性比对Ru-CYM大约高20倍。Ru-THA和Ru-CYM的加合物对DNA在体外的构象、热力学稳定性和聚合作用具有相反的影响。此外，Ru-CYM的加合物比Ru-THA的加合物更有效地从DNA上移除。有趣的是，与顺铂链内交联相比，哺乳动物核苷酸切除修复系统对钌加合物的切除效率较低。