Further insight into the DNA recognition mechanism of trabectedin from the differential affinity of its demethylated analogue ecteinascidin ET729 for the triplet DNA binding site CGA

J Med Chem. 2006 Nov 16;49(23):6925-9. doi: 10.1021/jm060640y.


Trabectedin and its N12-demethylated analogue ET729 bind covalently to the central guanine of selected DNA triplets. Although both drugs equally target several sites, including AGA, we show that covalent modification of CGA is only achieved by ET729. By means of molecular dynamics simulations of the precovalent complexes, we explain in atomic detail how such a simple structural modification brings about this notable change in the DNA-binding selectivity profiles of these two drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / chemistry*
  • Binding Sites
  • DNA / chemistry*
  • Dioxoles / chemistry*
  • Isoquinolines / chemistry*
  • Models, Molecular*
  • Nucleic Acid Conformation
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines / chemistry*
  • Trabectedin


  • Antineoplastic Agents, Alkylating
  • Dioxoles
  • Isoquinolines
  • Tetrahydroisoquinolines
  • ecteinascidin 729
  • DNA
  • Trabectedin