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Bioorg Med Chem Lett. 2005 Nov 15;15(22):5016-21.

Structure-based design of 7-carbamate analogs of geldanamycin.

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1
Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA.

Abstract

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.

PMID:
16165354
DOI:
10.1016/j.bmcl.2005.08.013
[Indexed for MEDLINE]
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