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Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90

DOI: 10.1038/nchem.1596 DOI Help
PMID: 23511419 PMID Help

Authors: Russell R. A. Kitson (School of Chemistry, University of Nottingham, University Park, Nottingham) , Chuan-hsin Chang (Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado) , Rui Xiong (Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado) , Huw E. L. Williams (School of Chemistry, University of Nottingham, University Park, Nottingham) , Adrienne L. Davis (School of Chemistry, University of Nottingham, University Park, Nottingham) , William Lewis (University of Nottingham) , Donna L. Dehn (Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado) , David Siegel (Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado) , Mark Roe (University of Sussex) , Chrisostomos Prodromou (Genome Damage and Stability Centre, Science Park Road, University of Sussex) , David Ross (Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado) , Christopher J. Moody (School of Chemistry, University of Nottingham, University Park, Nottingham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemistry , VOL 5 (4) , PAGES 307 - 314

State: Published (Approved)
Published: March 2013
Diamond Proposal Number(s): 8015

Abstract: The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, the toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. Here, we report an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.

Journal Keywords: Antineoplastic; Benzoquinones; Cell; Tumor; Cell; Chromatography; Thin; Crystallography; X-Ray; Drug; Female; HSP90; Human; Humans; Immunoblotting; Lactams; Macrocyclic; Models; Molecular; Protein; Stereoisomerism; Structure-Activity; Yeasts

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: No

Added On: 18/03/2014 17:34

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