Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents

J Med Chem. 2018 Nov 21;61(22):9908-9930. doi: 10.1021/acs.jmedchem.8b00639. Epub 2018 Oct 31.

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)-DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC50 value of 7 μM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future efforts for the discovery of natural product-based TOP1 and TDP1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • DNA Cleavage / drug effects
  • DNA Topoisomerases, Type I / chemistry
  • DNA Topoisomerases, Type I / metabolism*
  • Drug Design*
  • Humans
  • Models, Molecular
  • Phenanthridines / chemical synthesis*
  • Phenanthridines / chemistry
  • Phenanthridines / pharmacology*
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / metabolism*
  • Protein Conformation
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology

Substances

  • Antineoplastic Agents
  • Phenanthridines
  • Phosphodiesterase Inhibitors
  • Topoisomerase I Inhibitors
  • oxynitidine
  • Phosphoric Diester Hydrolases
  • tyrosyl-DNA phosphodiesterase
  • DNA Topoisomerases, Type I
  • TOP1 protein, human