467214-20-6Relevant articles and documents
Synthesis and biological activities of novel 17-aminogeldanamycin derivatives
Tian, Zong-Qiang,Liu, Yaoquan,Zhang, Dan,Wang, Zhan,Dong, Steven D.,Carreras, Christopher W.,Zhou, Yiqing,Rastelli, Giulio,Santi, Daniel V.,Myles, David C.
, p. 5317 - 5329 (2004)
A library of over sixty 17-alkylamino-17-demethoxygeldanamycin were synthesized. Their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility, were measured. The structure-activity relationships of binding affinity to Hsp90 and cytotoxicity in SKBr3 cells are discussed. Geldanamycin interferes with the action of heat shock protein 90 (Hsp90) by binding to the N-terminal ATP binding site and inhibiting an essential ATPase activity. In a program directed toward finding potent, water soluble inhibitors of Hsp90, we prepared a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogs, and compared their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility. Over 20 analogs showed cell growth inhibition potencies similar to that of 17-allylamino-17-demethoxygeldanamycin (17-AAG), the front-runner geldanamycin analog that is currently in multiple clinical trials. Many of these analogs showed water solubility properties that were desirable for formulation. One of the most potent and water-soluble analogs in the series was 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG), which was independently prepared by the NCI and will soon enter clinical trials. Importantly, the binding affinity of these analogs to the molecular target Hsp90 does not correlate well with their cytotoxicity in SKBr3 cells.
Structure-based design of 7-carbamate analogs of geldanamycin
Rastelli, Giulio,Tian, Zong-Qiang,Wang, Zhan,Myles, David,Liu, Yaoquan
, p. 5016 - 5021 (2007/10/03)
The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl) amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive.
