Investigating lipophilicity and hydrogen bonding properties of functionalised aliphatic compounds

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.

Who might benefit from this research?
In the first place, these are life-sciences related industries; the work has significant implications for the agrochemical and pharmaceutical industries (It is worth mentioning that >20% of current drugs, and >40% of agrochemicals are fluorinated). The materials industry will also benefit (eg liquid crystal based applications).

How might they benefit?
Our work deals with measuring and explaining effects of fluorination on important properties, with a focus on novel aspects (eg conformers). The data and understandings that we will generate will be used by industry and academia in their discovery processes where hydrogen bonding and lipophilicity are of importance.

Summary of Impacts:
Economic impact - drug discovery
We expect that economic impact will be realised through better information [eg regarding lipophilicity control], leading to better decisions, resulting in shorter development times in drug development, generating better-quality compounds etc. This will benefit the pharmaceutical industry, which represents a substantial economic activity in the UK: this is evidenced by some quotes below from the The Association of the British Pharmaceutical Industry (ABPI) website:
* In 2012, the pharmaceutical sector's contribution to the balance of trade was the third greatest of nine major industrial sectors.
* The pharmaceutical sector has, over the past decade, generated an ever-widening trade surplus, reaching a little over £2.8 billion in 2013.
* The pharmaceutical industry contributes more to the UK economy than would be possible if other industrial sectors used the same resources.
Hence, this fully conforms with the "Productivity" priority as explained in the EPSRC 2016 Delivery Plan.
In addition, there is much research ongoing in academia related to early drug discovery, development of new therapeutics, and generally the discovery of molecules ("probes" that can be used to study enzymes or biological processes). The MRC has specific academic programmes for drug development ultimately aimed at exploitation. Facilitation of these processes will thus impact positively on such efforts.

People:
This multidisciplinary project will be a fertile training ground for the PDRA, the associated PhD student, and the number of Southampton Undergraduate Project students who will contribute to this work. Thorough understanding of medicinal chemistry principles, organic synthesis, analytical and physical organic aspects are in demand by employers.

Societal impact.
Our work has the potential to benefit the quality of life if the development of novel therapeutics is accelerated (as to be approved, a novel drug must show a benefit over existing drugs). Hence, this innately relates to the EPSRC "Health" National Priority area (2016 Delivery Plan).
This will eventually benefit the NHS. Again, a quote from the The Association of the British Pharmaceutical Industry (ABPI) website: "Increasingly, pharmaceutical companies work with the NHS to ensure local health priorities are met, patient outcomes are improved and local NHS organisations can meet their objectives and these joint-working projects ensure a win:win: win for patients, the NHS and the industry."

It is important to communicate relevant research to the wider public: we will endeavor to have our methodology taken up by industry, as explained in the Pathways to Impact. If successful, then a news story will be produced which will be used in outreach activities (eg at open days or college visits). Such a 'story' would be very suitable to relate to the wider public, as the concepts involved will be easily explained, and the insight that indeed, pure academic research, in this instance, can be taken up by industry, and that results will benefit the Society at large. With the contemporary undercurrent of denouncing "experts", a story like this will contribute to the public's support for academic funding.