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Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol

journal contribution
posted on 2023-06-08, 09:23 authored by Nicolas Proisy, Swee Y Sharp, Kathy Boxall, Stephen Connelly, S Mark Roe, Chrisostomos ProdromouChrisostomos Prodromou, Alexandra M Z Slawin, Laurence PearlLaurence Pearl, Paul Workman, Christopher J Moody
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.

History

Publication status

  • Published

Journal

Chemistry & Biology

ISSN

1074-5521

Publisher

Elsevier

Issue

11

Volume

13

Page range

1203-1215

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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