title: Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives as novel small molecule chaperone amplifiers.
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).
authors.affiliation: Department of Chemistry, CytRx Corporation, 3030 Bunker Hill Street, Suite 101, San Diego, CA 92109, USA. yuefen.zhou@gmail.com
authors.forename: Yuefen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Linyi
authors.initials: L
authors.lastname: Wei
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Brady
authors.forename: P S
authors.initials: PS
authors.lastname: Murali Mohan Redddy
authors.forename: Tram
authors.initials: T
authors.lastname: Nguyen
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Au
authors.forename: Il Sang
authors.initials: IS
authors.lastname: Yoon
authors.forename: Gary
authors.initials: G
authors.lastname: Yip
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Jack R
authors.initials: JR
authors.lastname: Barber
authors.forename: Shi Chung
authors.initials: SC
authors.lastname: Ng
mesh_terms: 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
chemical_list: 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