Synthesis of 4‐Deoxy‐4‐Fluoro‐d‐Sedoheptulose: A Promising New Sugar to Apply the Principle of Metabolic Trapping

Abstract

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.