Structure-based design of 7-carbamate analogs of geldanamycin

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.