6-Substituted 6H-dibenzo[c,h][2,6]naphthyridin-5-ones: reversed lactam analogues of ARC-111 with potent topoisomerase I-targeting activity and cytotoxicity

Bioorg Med Chem. 2006 May 1;14(9):3131-43. doi: 10.1016/j.bmc.2005.12.028. Epub 2006 Jan 18.

Abstract

6-Substituted 8,9-dimethoxy-2,3-methylenedioxy-6H-dibenzo[c,h][2,6]naphthyridin-5-ones were synthesized and evaluated for topoisomerase I-targeting activity and cytotoxicity. Several of these reversed lactam analogues of ARC-111 exhibited exceptional cytotoxicity with IC50 values ranging from 0.5 to 3.0 nM. In contrast to topotecan, no resistance was observed with several of these reversed lactam analogues in tumor cell lines that overexpressed the efflux transporters MDR1 or BCRP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / chemistry
  • Benzene / chemistry*
  • Camptothecin / pharmacology
  • Cell Line
  • Cell Proliferation / drug effects
  • DNA / metabolism
  • DNA Topoisomerases, Type I / metabolism*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • Humans
  • Lactams / chemistry*
  • Molecular Structure
  • Naphthyridines / chemical synthesis
  • Naphthyridines / chemistry*
  • Naphthyridines / pharmacology*
  • Naphthyridines / toxicity
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors*

Substances

  • Amides
  • Enzyme Inhibitors
  • Lactams
  • Naphthyridines
  • Topoisomerase I Inhibitors
  • DNA
  • DNA Topoisomerases, Type I
  • Benzene
  • Camptothecin