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Details of Grant 

EPSRC Reference: EP/P019943/1
Title: Investigating lipophilicity and hydrogen bonding properties of functionalised aliphatic compounds
Principal Investigator: Linclau, Professor B
Other Investigators:
Williamson, Dr PTF
Researcher Co-Investigators:
Project Partners:
Nantes University
Department: School of Chemistry
Organisation: University of Southampton
Scheme: Standard Research
Starts: 01 April 2017 Ends: 31 March 2020 Value (£): 387,478
EPSRC Research Topic Classifications:
Analytical Science Chemical Structure
EPSRC Industrial Sector Classifications:
Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Panel DatePanel NameOutcome
24 Jan 2017 EPSRC Physical Sciences - January 2017 Announced
Summary on Grant Application Form
The process of designing molecules in order to optimise their properties (whether at the functional group level, the molecular level, supramolecular or macroscopic level) has achieved considerable levels of sophistication. In this context, selective fluorination of organic compounds has been one of the chemist's favourite tools to prevent undesirable properties/events (eg degradation), or to fine-tune desired ones (eg acid/basicity, conformation). This is because of the high electronegativity and non-polarisability of the fluorine atom and of the resulting highly polarised and strong carbon-fluorine bond. This very active research area has resulted in an ever-increasing understanding of how to profit from these special characteristics.

Our past research has led to novel instruments and novel insights, which inspired us to novel exciting and innovative research. The main properties we will investigate are hydrogen bonding and lipophilicity (which is a measure of cell membrane permeability). Hydrogen bonding is the most important specific non-covalent (non-fixed, temporary) interaction between a molecule and its local environment, and so it is of utmost relevance in ligand-protein binding (potency of a compound), supramolecular chemistry and catalysis. The potency of a compound describes how effective a molecule is once it reaches its target. But, the lipophilicity of a compound is a main factor that determines how effective a it is at reaching its target. Hence, potency and lipophilicity are the most important properties of bioactive compounds (probes, diagnostics and drugs).

Previous EPSRC-funded research by our group led to a novel way to measure lipophilicity of fluorinated compounds (which is defined as the partition coefficient of a compound in an octanol/water biphasic mixture). Not only is our new technique more accurate and straightforward than existing methods; an additional major benefit is that no UV-activity is required. This now gives us an exciting opportunity to study aliphatic organic compounds (which do not have aromatic rings, which are UV active). These aliphatic compounds are being increasingly used in drug development, but it is not easily possible to measure their lipophilicity using standard industry methods.

Furthermore, while the partition coefficient is the de facto standard for membrane permeability assessment, data regarding the actual partitioning of compounds into lipid bilayers is more scarce. Using a novel form of 19F solid state NMR we will be able to assess how the partition coefficient relates to partitioning into the native bilayer, including the influence of fluorination.

We also want to expand our research from fluorohydrins to the vitally important aliphatic amines (these are found in most drugs), in order to study the pH-dependent influence of fluorination on their lipophilicity, and of amides, where our technique allows us to investigate completely novel aspects, such as lipophilicity of conformers (which are different orientations of a molecule in space). This will be extended to sugar anomers (which are different sugar forms). We will also extend the methodology scope, both widening the lipophilicity range, and using it to test non-fluorinated compounds.

Previously, we have also investigated the hydrogen bond donating capacity of aliphatic alcohols. Given this success, we intend to expand our research to amines and amides. We also want to investigate the effect intramolecular hydrogen bonding involving fluorine has on lipophilicity. Our technique means we are uniquely placed to do this.

Our proposed research will significantly increase our understanding of the impact that fluorination has on two very important properties in a class of compounds that have increasing importance in the life sciences, in chemistry, and in materials chemistry. It will further cement the importance of our lipophilicity methodology through expanding its scope and number of applications.
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Organisation Website: http://www.soton.ac.uk