Synthesis and Demonstration of the Biological Relevance of sp3-rich Scaffolds Distantly Related to Natural Product Frameworks

Research output: Contribution to journalArticlepeer-review

Authors

  • Daniel J. Foley
  • Patrick M. Collins
  • Richard G. Doveston
  • Anthony Aimon
  • Romain Talon
  • Ian Churcher
  • Frank von Delft
  • Stephen P. Marsden
  • Adam Nelson

Colleges, School and Institutes

External organisations

  • University of Leeds
  • Diamond Light Source
  • University of Oxford
  • GlaxoSmithKline

Abstract

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top-down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3-rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.

Details

Original languageEnglish
Pages (from-to)15227-15232
JournalChemistry: A European Journal
Volume23
Issue number60
Early online date6 Oct 2017
Publication statusPublished - 26 Oct 2017

Keywords

  • chemical biology , fragments , molecular diversity , natural products , proteins