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Inhibition of Hsp90 with Resorcylic Acid Macrolactones: Synthesis and Binding Studies
Author(s) -
Day James E. H.,
Sharp Swee Y.,
Rowlands Martin G.,
Aherne Wynne,
Lewis William,
Roe S. Mark,
Prodromou Chrisostomos,
Pearl Laurence H.,
Workman Paul,
Moody Christopher J.
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201001119
Subject(s) - natural product , hydroxymethyl , stereochemistry , chemistry , substituent , hsp90 inhibitor , metathesis , hsp90 , chemical synthesis , total synthesis , salt metathesis reaction , combinatorial chemistry , heat shock protein , organic chemistry , biochemistry , in vitro , polymerization , gene , polymer
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.