The 3F Library: Fluorinated Fsp3-Rich Fragments for Expeditious 19F NMR Based Screening
| Autor: | Mads Hartvig Clausen, Hengxi Zhang, Ida S. A. Jensen, Nikolaj Sten Troelsen, Diego Gonzalez‐Romero, Katarzyna J. Śniady, Ana Cuenda, Charlotte Held Gotfredsen, Faranak Nami, Elena Shanina, Daniela Danková, Christoph Rademacher |
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| Přispěvatelé: | Villum Fonden, Max Planck Society, Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2020 |
| Předmět: |
Fragment-based drug discovery
Chemistry Drug discovery 010405 organic chemistry Philosophy Library science General Chemistry Computational biology Nuclear magnetic resonance spectroscopy General Medicine Fluorine 010402 general chemistry 01 natural sciences Catalysis 0104 chemical sciences NMR spectroscopy Fragment (logic) Molecular diversity Proton NMR Christian ministry Synthesis design Biological evaluation |
| Zdroj: | Angewandte Chemie, International Edition Angewandte Chemie Digital.CSIC. Repositorio Institucional del CSIC instname 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 International Edition, vol. 59, no. 6, pp. 2204-2210 . https://doi.org/10.1002/anie.201913125 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, vol. 131, no. 6, pp. 2224-2230 . https://doi.org/10.1002/ange.201913125 |
| DOI: | 10.1002/anie.201913125 |
| Popis: | 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, 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 NMR and subsequent 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 collection is the first synthetic fragment library tailor‐made for 19F NMR screening and the results demonstrate that the approach should find broad application in the FBDD community. We are grateful to DTU Chemistry for an academic excellence PhD scholarship for NST. The NMR Center • DTU and the VillumFoundation are acknowledged for access toNMR spectrometers. CR, HZ, and ES thank the DFG (RA1944/7-1) and the Max Planck Society for support. This work was supported by a grant from the Spanish Ministry ofScience and Innovation (SAF2016-79792R) to AC and DGR. We thank Dr. Kasper Enemark-Rasmussen and Charlie Johansen for expert technical assistance and Anastasia Richter, Mie Larsen, Sanne Møller, Thomas Klevin, Joakim Svensson, Julie Forchhammer, Pernille Christensen, and Ana Laura da Silva for synthesis and analysis of some fragments. |
| Databáze: | OpenAIRE |
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