Cellular Fucosylation Inhibitors Based on Fluorinated Fucose-1-phosphates*
Johan F A Pijnenborg1, Eline A Visser1, Marek Noga2
1Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525AJ, Nijmegen, The Netherlands.
Abstract:
Fucosylation of glycans impacts a myriad of physiological and pathological processes. Inhibition of fucose expression emerges as a potential therapeutic avenue for example in cancer, inflammation, and infection. In this study, we found that protected 2-fluorofucose 1-phosphate efficiently inhibits cellular fucosylation with a four to seven times higher potency than known inhibitor 2FF, independently of the anomeric stereochemistry. Nucleotide sugar analysis revealed that both the α- and β-GDP-2FF anomers are formed inside the cell. In conclusion, we developed A2FF1P and B2FF1P as potent new tools for studying the role of fucosylation in health and disease and they are potential therapeutic candidates.
Insights
We developed two new compounds, A2FF1P and B2FF1P, that potently inhibit cellular fucosylation. These compounds are promising tools for studying fucosylation in diseases like cancer and infection.
Area of Science:
- Biochemistry
- Glycobiology
- Medicinal Chemistry
Background:
- Fucosylation, the addition of fucose to glycans, plays a critical role in numerous physiological and pathological processes.
- Inhibiting fucose expression is a promising therapeutic strategy for conditions including cancer, inflammation, and infection.
Purpose of the Study:
- To develop novel inhibitors of cellular fucosylation.
- To evaluate the potency and mechanism of action of these new inhibitors compared to existing ones.
Main Methods:
- Synthesis of protected 2-fluorofucose 1-phosphate (2FF1P) derivatives.
- Assessment of cellular fucosylation inhibition potency.
- Nucleotide sugar analysis to determine intracellular anomer formation.
Main Results:
- Protected 2-fluorofucose 1-phosphate (2FF1P) demonstrated significantly higher potency (4-7 times) in inhibiting cellular fucosylation compared to the known inhibitor 2FF.
- Both α- and β-anomers of GDP-2FF were identified intracellularly, indicating their formation within the cell.
- The inhibitory potency was independent of the anomeric stereochemistry of the 2FF1P compounds.
Conclusions:
- A2FF1P and B2FF1P are potent inhibitors of cellular fucosylation.
- These compounds serve as valuable tools for investigating the role of fucosylation in health and disease.
- A2FF1P and B2FF1P represent potential therapeutic candidates for fucosylation-related diseases.
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