Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety

Bioorg Med Chem. 2015 May 1;23(9):2044-52. doi: 10.1016/j.bmc.2015.03.020. Epub 2015 Mar 12.

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy based on Top1 poison-mediated DNA damage. Several novel benzopentathiepines were synthesized and tested as inhibitors of TDP1 using a new oligonucleotide-based fluorescence assay. The benzopentathiepines have IC₅₀ values in the range of 0.2-6.0 μM. According to the molecular modeling, the conformational flexibility of the dibutylamine group of the most effective inhibitor (3d) allows it to occupy an advantageous position for effective binding compared to its cyclic counterparts. The study of cytotoxicity of these compounds revealed that all compounds cause an apoptotic cell death in MCF-7 and Hep G2 cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated.

Keywords: Molecular modeling; Pentathiepine; TDP1; TDP1 inhibitor; Tyrosyl-DNA phosphodiesterase 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dibenzothiepins / chemical synthesis
  • Dibenzothiepins / chemistry
  • Dibenzothiepins / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Structure-Activity Relationship

Substances

  • Dibenzothiepins
  • Phosphodiesterase Inhibitors
  • Phosphoric Diester Hydrolases
  • TDP1 protein, human