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J Org Chem. 2009 Jul 3;74(13):4697-704. doi: 10.1021/jo900278g.

Synthesis and evaluation of radamide analogues, a chimera of radicicol and geldanamycin.

Author information

1
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, Kansas 66045-7563, USA.

Abstract

Previously, we reported the Hsp90 inhibitory activity of radamide, an open chain amide chimera of geldanamycin and radicicol. Attempts to further expand upon structure-activity relationships for this class of Hsp90 inhibitors led to the preparation of a series of radamide analogues focused on differing tether lengths and quinone mimics. In addition, the cup-shaped conformation adopted by the two natural products when bound to the Hsp90 N-terminal ATP binding pocket suggests that conformationally biased compounds may demonstrate improved binding and inhibition. The preparation and evaluation of radamide analogues with cis/trans alpha,beta-unsaturated amides yielded compounds that exhibit improved antiproliferative activity. In addition, several analogues demonstrated the ability to induce degradation of Hsp90-dependent oncogenic signaling proteins in vitro, a hallmark of Hsp90 N-terminal inhibition.

PMID:
19492825
PMCID:
PMC2844856
DOI:
10.1021/jo900278g
[Indexed for MEDLINE]
Free PMC Article

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