Inhibition of Hsp90 with resorcylic acid macrolactones: synthesis and binding studies

Day, James E H, Sharp, Swee Y, Rowlands, Martin G, Aherne, Wynne, Lewis, William, Roe, S Mark, Prodromou, Chrisostomos, Pearl, Laurence H, Workman, Paul and Moody, Christopher J (2010) Inhibition of Hsp90 with resorcylic acid macrolactones: synthesis and binding studies. Chemistry - A European Journal, 16 (34). pp. 10366-10372. ISSN 0947-6539

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A series of resorcylic acid macrolactones, analogues of the natural product radicicol has 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 acylation of an ortho-toluic acid dianion, esterification, followed by a ring-closing metathesis to form the macrocycle. Subsequent manipulation of the protected hydroxymethyl side chain allows access to a range of new analogues following de-protection of the two phenolic groups. Co-crystallization of one of the new macrolactones with the N-terminal domain of yeast Hsp90 confirms that it binds in a similar way to the natural product radicicol and to our previous synthetic analogues, but that the introduction of the additional hydroxymethyl substituent appears to result in an unexpected change in conformation of the macrocyclic ring. As a result of this conformational change, the compounds bound less favorably to Hsp90.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Mark Roe
Date Deposited: 06 Feb 2012 21:12
Last Modified: 05 Mar 2015 07:37
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