title: Synthetic ansamycins prepared by a ring-expanding Claisen rearrangement. Synthesis and biological evaluation of ring and conformational analogues of the Hsp90 molecular chaperone inhibitor geldanamycin.
abstract: A series of ansa-quinones has been prepared by chemical synthesis, and evaluated by biological techniques. Thus, 19-membered ansa-lactams, simplified analogues of the naturally occurring Hsp90 molecular chaperone inhibitor geldanamycin, were obtained by concise routes, the key steps being the combination of a ring-closing metathesis to give a 17-membered ring followed by Claisen rearrangement to effect ring expansion. The methodology was also used to prepare an "unnatural" 18-membered ring analogue. In ATPase enzyme assays, the synthetic ansa-quinones were weak inhibitors of Hsp90.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham, UK NG7 2RD.
authors.forename: Christopher S P
authors.initials: CS
authors.lastname: McErlean
authors.forename: Nicolas
authors.initials: N
authors.lastname: Proisy
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Davis
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Boland
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Alexandra M Z
authors.initials: AM
authors.lastname: Slawin
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moody
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology; D003500:Cyclization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D000251:Adenosine Triphosphatases; C001277:geldanamycin