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.
Yuefen Zhou  1 ,  Linyi Wei ,  Thomas P Brady ,  P S Murali Mohan Redddy ,  Tram Nguyen ,  Jinhua Chen ,  Qingyan Au ,  Il Sang Yoon ,  Gary Yip ,  Bin Zhang ,  Jack R Barber ,  Shi Chung Ng
Affiliations
  • 1. Department of Chemistry, CytRx Corporation, 3030 Bunker Hill Street, Suite 101, San Diego, CA 92109, USA. [email protected]
PMID: 19502057 DOI: 10.1016/j.bmcl.2009.05.073
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).