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

Affiliation

1 Department of Chemistry, CytRx Corporation, 3030 Bunker Hill Street, Suite 101, San Diego, CA 92109, USA. yuefen.zhou@gmail.com

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).

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