Proisy, Nicolas, Sharp, Swee Y, Boxall, Kathy, Connelly, Stephen, Roe, S Mark, Prodromou, Chrisostomos, Slawin, Alexandra M Z, Pearl, Laurence H, Workman, Paul and Moody, Christopher J (2006) Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chemistry and Biology, 13 (11). pp. 1203-1215. ISSN 1074-5521

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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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Biochemistry
Depositing User:	Mark Roe
Date Deposited:	06 Feb 2012 21:14
Last Modified:	05 Mar 2015 07:40
URI:	http://sro.sussex.ac.uk/id/eprint/30379

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