In recent years, we developed a toolbox of heavy isotope containing compounds, which serve as metabolic amino acid precursors in the E. coli-based overexpression of aromatic residue labeled proteins. Our labeling techniques show excellent results both in terms of selectivity and isotope incorporation levels. They are additionally distinguished by low sample production costs and meet the economic demands to further implement protein NMR spectroscopy as a routinely used method in drug development processes. Different isotopologues allow for the assembly of optimized protein samples, which fulfill the requirements of various NMR experiments to elucidate protein structures, analyze conformational dynamics, or probe interaction surfaces. In the present article, we want to summarize the precursors we developed so far and give examples of their special value in the probing of protein–ligand interaction.
We describe the synthesis of planar-chiral diferrocene compounds 4, 7 and 12, intended as key precursors for a new family of asymmetric catalyst ligands with less complex structures than their popular equivalents. In contrast to conventional 1,2-disubstituted ferrocenes containing center-chiral and planar-chiral elements, these compounds are purely planar-chiral due to the absence of α-substiuted ethyl groups. The title compounds 4, 7 and 12 were obtained from known precursors in 87%, 59% and 60% yields, respectively.
Fluorinated carbohydrates are important tools for understanding the deregulation of metabolic fluxes and pathways. Fluorinating specific positions within the sugar scaffold can lead to enhanced metabolic stability and subsequent metabolic trapping in cells. This principle has, however, never been applied to study the metabolism of the rare sugars of the pentose phosphate pathway (PPP). Thus, we designed and synthesized two fluorinated derivatives of D‐sedoheptulose: 4‐deoxy‐4‐fluoro‐D‐sedoheptulose (4DFS) and 3deoxy‐3‐fluoro‐D‐sedoheptulose (3DFS). We show that both sugars are taken up by human fibroblasts but that only 4DFS is phosphorylated. We could further show that fluorination of Dsedoheptulose at C‐4 effectively halts the enzymatic degradation by transaldolase and transketolase. 4DFS thus has a high potential as a new PPP imaging probe based on the principle of metabolic trapping. Therefore, we further present the synthesis of potential radiolabeling precursors for 4DFS for future radiofluorinations with fluorine‐18.
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