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Targeting the Hsp90 Molecular Chaperone with Novel Macrolactams. Synthesis, Structural, Binding, and Cellular Studies

DOI: 10.1021/cb200196e DOI Help
PMID: 21932796 PMID Help

Authors: James E. H. Day (School of Chemistry, University of Nottingham, U.K.) , Swee Y. Sharp (Cancer Research UK Cancer Therapeutics Unit, U.K.) , Martin G. Rowlands (Cancer Research UK Cancer Therapeutics Unit, U.K.) , Wynne Aherne (Cancer Research UK Cancer Therapeutics Unit, U.K.) , Angela Hayes (Cancer Research UK Cancer Therapeutics Unit, U.K.) , Florence I. Raynaud (Cancer Research UK Cancer Therapeutics Unit, U.K.) , William Lewis (University of Nottingham) , S. Mark Roe (The Institute of Cancer Research, Chester Beatty Laboratories, U.K.) , Chrisostomos Prodromou (The Institute of Cancer Research, Chester Beatty Laboratories, U.K.) , Laurence H. Pearl (The Institute of Cancer Research, Chester Beatty Laboratories, U.K.) , Paul Workman (Cancer Research UK Cancer Therapeutics Unit, U.K.) , Christopher J. Moody (School of Chemistry, University of Nottingham, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 6 (12) , PAGES 1339 - 1347

State: Published (Approved)
Published: December 2011
Diamond Proposal Number(s): 6385

Abstract: A series of resorcylic acid macrolactams, nitrogen analogues of the naturally occurring macrolactone radicicol, have been prepared by chemical synthesis and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. The synthesis involves, as key steps, ring opening of an isocoumarin intermediate, followed by a ring- closing metathesis reaction to form the macrocycle. Subsequent manipulation of the ester group into a range of amides allows access to a range of new macrolactams following deprotection of the two phenolic groups. These new resorcylic acid lactams exhibit metabolic stability greater than that of related lactone counterparts, while co-crystallization of three macrolactams with the N-terminal domain ATP site of Hsp90 conforms that they bind in a similar way to the natural product radicicol and to our previous synthetic lactone analogues. Interestingly, however, in the case of the N- benzylamide, additional binding to a hydrophobic pocket of the protein was observed. In biological assays, the new macrocyclic lactams exhibit a biological pro\ufb01le equivalent or superior to that of the related lactones and show the established molecular signature of Hsp90 inhibitors in human colon cancer cells.

Journal Keywords: Crystallography; X-Ray; HCT116; HSP90; Humans; Lactams; Macrocyclic; Macrolides; Microsomes; Liver; Models; Molecular

Subject Areas: Medicine, Chemistry, Biology and Bio-materials


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

Added On: 28/03/2012 10:40

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