Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol.
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.
Proisy
Nicolas
N
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.
Sharp
Swee Y
SY
Boxall
Kathy
K
Connelly
Stephen
S
Roe
S Mark
SM
Prodromou
Chrisostomos
C
Slawin
Alexandra M Z
AM
Pearl
Laurence H
LH
Workman
Paul
P
Moody
Christopher J
CJ
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
D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; D000251:Adenosine Triphosphatases; C035359:monorden