Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives as novel small molecule chaperone amplifiers

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4303-7. doi: 10.1016/j.bmcl.2009.05.073. Epub 2009 May 27.

Abstract

Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives were investigated as novel small molecule amplifiers of heat shock factor 1 transcriptional activity. Lead optimization led to the discovery of compound 4A-13, which displayed potent HSF1 activity under mild heat stress (EC(50)=2.5microM) and significant cytoprotection in both rotenone (EC(50)=0.23microM) and oxygen-glucose deprivation cell toxicity models (80% protection at 2.5microM).

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods
  • DNA-Binding Proteins / chemistry
  • Drug Design
  • Glucose / chemistry
  • Heat Shock Transcription Factors
  • Humans
  • Models, Chemical
  • Molecular Chaperones / chemistry
  • Neurodegenerative Diseases / drug therapy
  • Oxygen / chemistry
  • Protein Conformation
  • Protein Folding
  • Pyrimidinones / chemical synthesis*
  • Rats
  • Rotenone / chemical synthesis*
  • Rotenone / pharmacology
  • Structure-Activity Relationship
  • Transcription Factors / chemistry
  • Triazines / chemistry*
  • Triazines / pharmacology
  • Uracil / analogs & derivatives*
  • Uracil / chemistry
  • Uracil / pharmacology

Substances

  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Hsf1 protein, rat
  • Molecular Chaperones
  • Pyrimidinones
  • Transcription Factors
  • Triazines
  • Rotenone
  • Uracil
  • Glucose
  • Oxygen