Targeting the Hsp90 chaperone: synthesis of novel resorcylic acid macrolactone inhibitors of Hsp90.
A series of benzo-macrolactones 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. A new synthesis of these resorcylic acid macrolactone analogues of the natural product radicicol is described in which the key steps are the acylation and ring opening of a homophthalic anhydride to give an isocoumarin, followed by a ring-closing metathesis to form the macrocycle. The methodology has been extended to a novel series of macrolactones incorporating a 1,2,3-triazole ring.
Day
James E H
JE
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
Sharp
Swee Y
SY
Rowlands
Martin G
MG
Aherne
Wynne
W
Workman
Paul
P
Moody
Christopher J
CJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D014230:Triazoles / Q000737:chemistry
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D014230:Triazoles; C035359:monorden