title: Inhibition of Hsp90 with resorcylic acid macrolactones: synthesis and binding studies.
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.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, UK.
authors.forename: James E H
authors.initials: JE
authors.lastname: Day
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Martin G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: Wynne
authors.initials: W
authors.lastname: Aherne
authors.forename: William
authors.initials: W
authors.lastname: Lewis
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moody
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D047028:Macrocyclic Compounds; D018942:Macrolides