Inhibition of Hsp90 with resorcylic acid macrolactones: synthesis and binding studies.
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.
Day
James E H
JE
School of Chemistry, University of Nottingham, University Park, UK.
Sharp
Swee Y
SY
Rowlands
Martin G
MG
Aherne
Wynne
W
Lewis
William
W
Roe
S Mark
SM
Prodromou
Chrisostomos
C
Pearl
Laurence H
LH
Workman
Paul
P
Moody
Christopher J
CJ
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
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D047028:Macrocyclic Compounds; D018942:Macrolides