Structural simplification of bioactive natural products with multicomponent synthesis. 3. Fused uracil-containing heterocycles as novel topoisomerase-targeting agents. Academic Article uri icon

start page

  • 2012

end page

  • 2021


  • After the initial discovery of antiproliferative and apoptosis-inducing properties of a camptothecin-inspired pentacycle based on a 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine scaffold, a library of its analogues as well as their oxidized planar counterparts were prepared utilizing a practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar antiproliferative potencies toward a panel of human cancer cell lines. Biochemical experiments are consistent with the dihydropyridine library members undergoing intracellular oxidation to the corresponding planar pyridines, which then inhibit topoisomerase II activity, leading to inhibition of proliferation and cell death. Because of facile synthetic preparation and promising antitopoisomerase activity, both the dihydropyridine and planar pyridine-based compounds represent a convenient starting point for anticancer drug discovery.

date/time value

  • 2011

Digital Object Identifier (DOI)

  • 10.1021/jm1009428

PubMed Identifier

  • 21388138


  • 54


  • 7


  • Antineoplastic Agents
  • Biological Agents
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II
  • Humans
  • Inhibitory Concentration 50
  • Topoisomerase II Inhibitors
  • Uracil