The 3F Library: Fluorinated Fsp3-rich Fragments for Expeditious 19F-NMR-based Screening

Nikolaj Sten Troelsen, Elena Shanina, Diego Gonzalez-Romero, Daniela Dankova, Ida S. A. Jensen, Katarzyna J. Sniady, Faranak Nami, Hengxi Zhang, Christoph Rademacher, Ana Cuenda, Charlotte H. Gotfredsen, Mads Hartvig Clausen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Fragment-based drug discovery is a popular method in academia and the pharmaceutical industry for the discovery of early lead candidates. Despite its wide-spread use, the approach still suffers from laborious screening workflows and a limited diversity in the fragments applied. Here we present the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges. The 3F library of 115 fluorinated, Fsp3-rich fragments is shape diverse and natural product-like with desirable physicochemical properties. The library is perfectly suited for rapid and efficient screening by NMR spectroscopy in a two-stage workflow of 19F- followed by 1H-NMR methods. Hits against four diverse protein targets are widely distributed among the fragment scaffolds in the 3F library and a 67% validation rate was achieved using secondary assays. This is the first synthetic fragment library tailor-made for 19F-NMR screening and our results underline that the approach should find broad application in the FBDD community.
Original languageEnglish
JournalAngewandte Chemie
Volume131
Issue number6
Pages (from-to)2224-2230
ISSN0044-8249
DOIs
Publication statusPublished - 2020

Keywords

  • Fluorine
  • Fragment-based drug discovery
  • Molecular diversity
  • NMR spectroscopy
  • Synthesis design

Cite this

Troelsen, N. S., Shanina, E., Gonzalez-Romero, D., Dankova, D., Jensen, I. S. A., Sniady, K. J., Nami, F., Zhang, H., Rademacher, C., Cuenda, A., Gotfredsen, C. H., & Clausen, M. H. (2020). The 3F Library: Fluorinated Fsp3-rich Fragments for Expeditious 19F-NMR-based Screening. Angewandte Chemie, 131(6), 2224-2230. https://doi.org/10.1002/ange.201913125