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The University of Southampton
Chemistry

Research project: Linclau: Polyfluorinated Carbohydrates

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The pronounced hydrophilicity of carbohydrates is an inherent significant contributor to the typically low affinity found for protein-carbohydrate interactions. This unfavorable factor has to be taken into account when developing inhibitors of carbohydrate processing enzymes or carbohydrate binding proteins starting from a carbohydrate structure, at least for non mechanism-based inhibitors. Carbohydrates are very important in Nature beyond a source of enery: they play a central role in many fundamental processes (eg cell-cell recognition), and glycosylation of proteins and natural products can significantly alter their stability and/or biological activity. Hence, the design of carbohydrate-based analogues with greater affinity to carbohydrate-recognising or processing proteins is of interest for use as probes or therapeutics.

We are interested in investigating an approach in which the carbohydrate ring is modified by extensive fluorination. The rationale for this approach is that the combination of aqueous desolvation of perfluoroalkylidene groups as well as attractive multipolar interactions mediated by the individual polar C–F bonds would positively contribute to the sugar binding affinity and selectivity. Such C–F mediated polar interactions have been recognised, and described in detail, by Diederich et al.

With synthetic methodology developed in the group (eg Angew. Chem. Int. Ed. 2004, 43, 5677; Org. Lett. 2008, 10, 3673; Org. Biomol. Chem. 2009, 7, 803; J. Org. Chem. 2016, 81, 4434), we have synthesised an extensive library of fluorosugars, examples shown in Figure 1.

 

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Figure 1

In a biological context, our group and collaborators have described the synthesis and biological evaluation of dideoxy-tetrafluorinated uridine diphosphate (UDP)-Gal analogues 1 and 2 (Figure 2) as inhibitors of the enzyme UDP-galactopyranose mutase (UGM)(Chem Eur J 2014, 20, 106). Inhibition assays and competition STD NMR experiments clearly showed that 2 possessed much higher affinities compared to its non-fluorinated parent, and that the tetrafluorinated structures occupied the same binding site. This was confirmed by structural studies using X-ray crystallography of the Mycobacterium tuberculosis UGM, which further revealed that binding of both 1 and 2 occurred with extensive substrate-enzyme interactions, including CF–F•••H2O interactions (J Am Chem Soc 2015, 137, 1230).

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Figure 2

Hence, with the obvious caveat that sugar C–OH for C–F replacement will result in a loss of hydrogen bond donating capacity at these positions, these results demonstrate the potential of tetrafluorinated derivatives for investigation as potential carbohydrate mimetics as inhibitors of carbohydrate processing enzymes.

We have also established the change in hydrophilicity/lipophilicity (logP) when OH groups are changed for CHF or CF2, using our newly developed methodology (Angew. Chem. Int. Ed. 2016, 55, 674 (VIP). 

Furthermore, we are investigating the conformation of such sugar derivatives (eg Carbohydrate Res. 2011, 346, 1129).

Research in the group regarding the synthesis, biological evaluation, lipophilicity determination and conformational studies of these kind of polyfluorinate sugars is ongoing.

 

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
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