Molecular drug design, synthesis and crystal structure determination of CuII-SnIV heterobimetallic core: DNA binding and cleavage studies

Eur J Med Chem. 2012 Mar:49:141-50. doi: 10.1016/j.ejmech.2012.01.005. Epub 2012 Jan 15.

Abstract

A novel heterobimetallic Cu(II)-Sn(IV) complex 1 bearing bioactive 1,10-phenanthroline pharmacophore ligand scaffold was synthesized and characterized by elemental analysis, IR, UV-vis spectroscopy, Mass (ESI and FAB) and X-ray crystallography. The in vitro DNA binding studies of complex 1 with CT DNA was carried out by various biophysical and molecular docking techniques which revealed that complex 1 binds to DNA through intercalation in the minor groove having AT-rich sequences. Complex 1 exhibits high chemical nuclease activity cleaving supercoiled pBR322 DNA via hydrolytic pathway which was further evidenced by T4 DNA ligase assay. The complex 1 shows high inhibitory activity against Topo I at a very low concentration (15 μM), suggesting that complex 1 is an efficient catalytic inhibitor of human Topo I and further validated by molecular docking studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Coordination Complexes / chemistry*
  • Coordination Complexes / pharmacology
  • Copper / chemistry*
  • Copper / pharmacology
  • Crystallography, X-Ray
  • DNA / chemistry
  • DNA / metabolism*
  • DNA Cleavage / drug effects*
  • DNA Topoisomerases, Type I / metabolism
  • Drug Design
  • Humans
  • Models, Molecular
  • Nucleic Acid Conformation
  • Phenanthrolines / chemistry*
  • Phenanthrolines / pharmacology
  • Tin / chemistry*
  • Tin / pharmacology
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology

Substances

  • Coordination Complexes
  • Phenanthrolines
  • Topoisomerase I Inhibitors
  • Tin
  • Copper
  • DNA
  • calf thymus DNA
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
  • 1,10-phenanthroline