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