title: Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol.
abstract: A series of benzo-macrolactones of varying ring size and conformation has been prepared by chemical synthesis and evaluated by structural and biological techniques. Thus, 12- to 16-membered lactones were obtained by concise routes, involving ring-closing metathesis as a key step. In enzyme assays, the 13-, 15-, and 16-membered analogs are good inhibitors, suggesting that they can adopt the required conformation to fit in the ATP-binding site. This was confirmed by cocrystallization of 13-, 14-, and 15-membered lactones with the N-terminal domain of yeast Hsp90, showing that they bind similarly to the "natural" 14-membered radicicol. The most active compounds in the ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human colon cancer cells and the established molecular signature of Hsp90 inhibition, i.e., depletion of client proteins with upregulation of Hsp70.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Proisy
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Stephen
authors.initials: S
authors.lastname: Connelly
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Alexandra M Z
authors.initials: AM
authors.lastname: Slawin
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: D000251:Adenosine Triphosphatases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D011487:Protein Conformation
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; D000251:Adenosine Triphosphatases; C035359:monorden