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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Calorimetry
  • DNA / chemistry*
  • DNA / drug effects
  • DNA Repair / drug effects
  • DNA-Directed RNA Polymerases / chemistry
  • DNA-Directed RNA Polymerases / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Sequence Data
  • Nucleic Acid Conformation* / drug effects
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacology
  • Ruthenium / chemistry*
  • Structure-Activity Relationship

Substances

  • Organometallic Compounds
  • Ruthenium
  • DNA
  • DNA-Directed RNA Polymerases