Synthesis and discovery of N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing uracil derivatives as potent human deoxyuridine triphosphatase inhibitors

J Med Chem. 2012 Apr 12;55(7):2960-9. doi: 10.1021/jm201627n. Epub 2012 Mar 26.


Recently, deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as part of a new strategy of 5-fluorouracil-based combination chemotherapy. We have initiated a program to develop potent drug-like dUTPase inhibitors based on structure-activity relationship (SAR) studies of uracil derivatives. N-Carbonylpyrrolidine- and N-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (12k) having excellent potencies (IC(50) = 0.15 μM). The X-ray structure of a complex of 16a and human dUTPase revealed a unique binding mode wherein its uracil ring and phenyl ring occupy a uracil recognition region and a hydrophobic region, respectively, and are stacked on each other. Compounds 12a and 16a markedly enhanced the growth inhibition activity of 5-fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC(50) = 0.27-0.30 μM), suggesting that our novel dUTPase inhibitors could contribute to the development of chemotherapeutic strategies when used in combination with TS inhibitors.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Floxuridine / pharmacology
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Pyrophosphatases / antagonists & inhibitors*
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Small Molecule Libraries
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thymidylate Synthase / antagonists & inhibitors
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis*
  • Uracil / chemistry
  • Uracil / pharmacology


  • Antineoplastic Agents
  • Pyrrolidines
  • Small Molecule Libraries
  • Floxuridine
  • Uracil
  • Thymidylate Synthase
  • Pyrophosphatases
  • dUTP pyrophosphatase
  • doxifluridine

Associated data

  • PDB/3ARA