Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives as novel small molecule chaperone amplifiers.
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).
Zhou
Yuefen
Y
Department of Chemistry, CytRx Corporation, 3030 Bunker Hill Street, Suite 101, San Diego, CA 92109, USA. yuefen.zhou@gmail.com
Wei
Linyi
L
Brady
Thomas P
TP
Murali Mohan Redddy
P S
PS
Nguyen
Tram
T
Chen
Jinhua
J
Au
Qingyan
Q
Yoon
Il Sang
IS
Yip
Gary
G
Zhang
Bin
B
Barber
Jack R
JR
Ng
Shi Chung
SC
D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004268:DNA-Binding Proteins / Q000737:chemistry; D015195:Drug Design; D005947:Glucose / Q000737:chemistry; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000737:chemistry; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D010100:Oxygen / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D011744:Pyrimidinones / Q000138:chemical synthesis*; D051381:Rats; D012402:Rotenone / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D018832:Molecular Chaperones; D011744:Pyrimidinones; D014157:Transcription Factors; D014227:Triazines; D012402:Rotenone; D014498:Uracil; D005947:Glucose; D010100:Oxygen