Lipophilicity of fluorinated carbohydrates and derivatives

S5.1 Glycomimetics
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 14:45 to 15:00

Bruno Linclau1

1University of Southampton, Southampton, United Kingdom

Lipophilicity is a much used parameter in drug development, and defined as the octanol-water partition coefficient. It is a measure for membrane permeability, and a proxy for solubility and ADME properties, which determine to a large degree dosing, and thus toxicity effects. Until recently, drug development was strongly focused on bioactivity optimisation, to the extent that lipophilicity of drug candidates was allowed to rise to unsuitable levels (referred to as “molecular obesity”). Indeed, increasing lipophilicity is correlated with stronger binding but it is also correlated with unfavourable solubility and ADME properties. Nowadays bioactivity and lipophilicity are optimised simultaneously in the drug discovery process. The introduction of fluorine in organic compounds is one of the ways to achieve this. 

On the contrary, carbohydrates are too hydrophilic, and we all know that the pharmaceutical industry is, in general, not keen to work with carbohydrates partly for that reason. However, the lipophilicity of carbohydrate derivatives is not well-established. In fact, there are, to the best of our knowledge, almost no such data in the literature, and lipophilicity is typically not included in protein-carbohydrate binding considerations. This may be due to the difficult lipophilicity measurement of (the non-UV active) carbohydrates.  

Sugar deoxyfluorination will increase lipophilicity, and we became interested in quantifying the extent of these expected changes. This led to the development of a suitable, convenient and accurate 19F NMR based direct logP determination method.[1] This will be explained in the presentation, followed by a discussion of results that include influence of sugar ring stereochemistry, fluorination position, fluorination motif, and anomeric configuration, on the sugar lipophilicity. We will also introduce the concept of “anomeric-specific lipophilicities” of reducing sugars, which will be discussed based on measured values.

We believe that these data provide an extra level of information that may be useful in the interpretation of binding affinity data of modified carbohydrates, and to the optimisation of physical properties of carbohydrate analogues to facilitate the application of carbohydrates in Medicine. 

  1. B. Linclau, Z. Wang, G. Compain, V. Paumelle, C. Q. Fontenelle, N. Wells, A. Weymouth-Wilson, Angew. Chem. Int. Ed. Engl. 2016, 55, 674.