Fluorine ligand-based NMR spectroscopy has emerged as a powerful screening tool for fragment-based drug discovery (FBDD). Compared to 1H NMR-based methods, 19F NMR screening offers several key advantages including increased sensitivity and simplicity. When using 1H NMR, screening cocktails are typically limited to five compound due to spectral overlap of signals and interference from solvents, buffers, or detergents. However, with fluorine the spectral range is much broader (~200 ppm) and as fluorinated molecules normally give rise to only one signal 19F NMR-based screening facilitates screening cocktails of up to 40 compounds. Unfortunately, the use of 19F NMR for screening in FBDD is currently limited by the limited availability and relatively low diversity of commercially available fluorinated fragments. Thus, to further investigate and contribute to the usefulness of 19F NMR-based screening in FBDD and at the same time developing new fragment scaffolds, we set out to synthesize a small and diverse library of fluorinated fragments. Based on a reagent-based diversity oriented synthetic strategy, we have constructed a highly three-dimensional library starting from similar and commercially available trifluoromethylated starting materials (Figure 1). Together with already existing fluorinated fragments, the fragments are screened against multiple targets using 19F NMR-based methods. We here present the synthesis of the fluorinated fragment library and the latest results from 19F NMR screening assays.

Synthesis and 19F NMR-based screening of a library of diverse and three-dimensional fluorinated fragments

256th National Meeting (2018)

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