Multiply Intercalator-Substituted Cu(II) Cyclen Complexes as DNA Condensers and DNA/RNA Synthesis Inhibitors

Inorg Chem. 2018 May 7;57(9):5004-5012. doi: 10.1021/acs.inorgchem.8b00027. Epub 2018 Apr 23.

Abstract

Many drugs that are applied in anticancer therapy such as the anthracycline doxorubicin contain DNA-intercalating 9,10-anthraquinone (AQ) moieties. When Cu(II) cyclen complexes were functionalized with up to three (2-anthraquinonyl)methyl substituents, they efficiently inhibited DNA and RNA synthesis resulting in high cytotoxicity (selective for cancer cells) accompanied by DNA condensation/aggregation phenomena. Molecular modeling suggests an unusual bisintercalation mode with only one base pair between the two AQ moieties and the metal complex as a linker. A regioisomer, in which the AQ moieties point in directions unfavorable for such an interaction, had a much weaker biological activity. The ligands alone and corresponding Zn(II) complexes (used as redox inert control compounds) also exhibited lower activity.

MeSH terms

  • Cell Line
  • Cell Survival / drug effects
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology*
  • Copper / chemistry*
  • Crystallography, X-Ray
  • DNA / biosynthesis*
  • DNA / chemistry
  • DNA Replication / drug effects*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Plasmids
  • RNA / biosynthesis*
  • RNA / chemistry
  • Structure-Activity Relationship

Substances

  • Coordination Complexes
  • RNA
  • Copper
  • DNA