The 3F Library: Fluorinated Fsp 3 -Rich Fragments for Expeditious 19 F NMR Based Screening.

Autor: Troelsen NS; Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kongens, Lyngby, Denmark., Shanina E; Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424, Potsdam, Germany.; Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany., Gonzalez-Romero D; Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus UAM, 28049, Madrid, Spain., Danková D; Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kongens, Lyngby, Denmark., Jensen ISA; Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kongens, Lyngby, Denmark., Śniady KJ; Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kongens, Lyngby, Denmark., Nami F; Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kongens, Lyngby, Denmark., Zhang H; Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424, Potsdam, Germany.; Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany., Rademacher C; Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424, Potsdam, Germany.; Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany., Cuenda A; Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus UAM, 28049, Madrid, Spain., Gotfredsen CH; NMR Center⋅DTU, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kongens, Lyngby, Denmark., Clausen MH; Center for Nanomedicine and Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kongens, Lyngby, Denmark.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2020 Feb 03; Vol. 59 (6), pp. 2204-2210. Date of Electronic Publication: 2019 Dec 17.
DOI: 10.1002/anie.201913125
Abstrakt: 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.
(© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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