Inhibition of Hsp90 with Resorcylic Acid Macrolactones: Synthesis and Binding Studies |
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Authors: | Dr. James E. H. Day Dr. Swee Y. Sharp Dr. Martin G. Rowlands Dr. Wynne Aherne Dr. William Lewis Dr. S. Mark Roe Dr. Chrisostomos Prodromou Prof. Dr. Laurence H. Pearl Prof. Dr. Paul Workman Prof. Dr. Christopher J. Moody |
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Affiliation: | 1. School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD (UK), Fax: (+44)?115‐951‐3564;2. Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey, SM2 5NG (UK);3. Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB (UK) |
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Abstract: | 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 deprotection 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. |
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Keywords: | anticancer agents enzyme inhibitors macrocycles macrocyclic compounds metathesis proteins |
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