The 3F Library: Fluorinated Fsp3‐Rich Fragments for Expeditious 19F NMR Based Screening. Issue 6 (17th December 2019)

• Record Type: Journal Article
• Authors: Troelsen, Nikolaj S.; Shanina, Elena; Gonzalez‐Romero, Diego; Danková, Daniela; Jensen, Ida S. A.; Śniady, Katarzyna J.; Nami, Faranak; Zhang, Hengxi; Rademacher, Christoph; Cuenda, Ana; Gotfredsen, Charlotte H.; Clausen, Mads H.
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 6(2020)
• Page Start: 2204
• Page End: 2210
• Publication Date: 2019-12-17
• Subjects: drug discovery -- fluorine -- molecular diversity -- NMR spectroscopy -- synthesis design; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201913125
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Fragment‐based drug discovery (FBDD) 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. Presented here is the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges. The 3F library of 115 fluorinated, Fsp 3 ‐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 19 F NMR and subsequent 1 H 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 collection is the first synthetic fragment library tailor‐made for 19 F NMR screening and the results demonstrate that the approach should find broad application in the FBDD community. Abstract : Taking the lead : A large library of fluorinated fragments was designed and synthesized to address the need for better sampling of chemical space and easier screening workflows. The incorporation of fluorine enabled efficient screening by 19 F NMR spectroscopy, which was demonstrated for screening against four disease‐relevant targets, providing a series of starting points for drug discovery.