Synthesis of Functionalized 2-(4-Hydroxyphenyl)-3-methylbenzofuran Allosteric Modulators of Hsp90 Activity

Sara Sattin, Matteo Panza, Francesca Vasile, Francesca Berni, Giulio Goti, Jiahui Tao, Elisabetta Moroni, David A. Agard, Giorgio Colombo, Anna Bernardi

Research output: Contribution to journalArticlepeer-review

Abstract

Hsp90 is a molecular chaperone that plays a pivotal role in the cell life cycle. ATP-regulated internal dynamics are critical to Hsp90 function and we recently demonstrated that these dynamics can be modulated in an allosteric fashion; the protein C-terminal domain (CTD) can be effectively targeted with a family of 2-phenyl-benzofuran derivatives. Here we describe the expansion of the initial library, reporting 28 new derivatives that explore the chemical space at opposite ends of the benzofuran scaffold. Interactions of the compounds with a full-length protein homolog were explored by Saturation Transfer Difference (STD) NMR spectroscopy. In this context we also report the interaction epitope of Novobiocin, a known CTD inhibitor.

Original languageEnglish
Pages (from-to)3349-3364
Number of pages16
JournalEuropean Journal of Organic Chemistry
Volume2016
Issue number20
DOIs
Publication statusPublished - 2016

Keywords

  • Allosteric modulators
  • Glycosylation
  • Heat shock proteins
  • Medicinal chemistry
  • Molecular dynamics
  • Oxygen heterocycles

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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