Partially fluorinated alkyl motifs for pharmaceuticals and agrochemicals research

The proposed research aims to explore the preparation of several small partially fluorinated motifs for appending to small organic molecules for use in bioactives discovery. The work will also extend to performance organic materials, specifically liquid crystals for displays.
Fluorine is often introduced into molecules during development to tune the physical properties of the molecule, or in the case of drugs, to improve in-vivo properties (pharmacokinetics). This has resulted in fluorine being introduced into about 20-30% of all bioactive products coming onto the market in the pharmaceuticals and agrochemicals sectors. Fluorine has the interesting property of being highly polarised (it is the most electronegative element) and it pulls electron density through sigma bonds (known as the inductive effect), and this has the effect of changing the overall polarity of the molecule, or changing the nature of neighbouring atoms eg making hydrogens more electropositive than usual. However the fluorine atom itself is very poor at interacting with adjacent molecules (weak intermolecular interactions). It is also relatively small and the next smallest atom after hydrogen that can be bound to carbon in a stable form (C-F bond is the strongest bond in organic chemistry). This combination of features makes fluorine an excellent tool for replacing hydrogen atoms on a molecule to tune its properties (by tugging electron density towards the fluorine), without changing the shape of the molecule too much, and without changing the nature of intermolecular interactions. When more than one fluorine is introduced, this can become problematic. Typically industry might introduce a CF3 group. This now is getting quite large. It is hydrophobic and it repels water, and it confers increased lipophilicity on the molecule. This can be good for binding to a particular protein target, but the molecule is less soluble in water and more soluble in lipid membranes, and it now has difficulty passing through membranes and being carried in the blood, until it gets to its target. So a good combination is to increase affinity for hydrophobic sites on a protein target, but to retain reasonable water solubility. Ideally if organic substituents can be introduced that are a little larger, but that do not increase lipophilicity (Log P), relative to Et or CH3, then such organic substituents would be attractive.
In this proposal we have identified four motifs that are novel, and posess these polar hydrophobic characteristics. Motifs 1 and 2 are oxygen and sulfur difluoroethyl ethers. We have devised methods to prepare them, and want to explore chemistry for introducing them into a range of building bocks, and medicinal like products. We will also systematically explore their polarity (Log Ps) and their metabolism (how the body may modify them, if at all).
Motifs 3 and 4 are cyclopropanes carrying three fluorines. They are polarised as they have two hydrogens (methylene group) with three electronegative fluorine atoms adjacent. In motif 4 there is an additional oxygen atom (also electronegative), polarising this motif further. These motifs are highly novel, but we have demonstrated that they can be readily prepared. The programme will explore their potential utility and properties with a focus on bioactive discovery programmes, and through this programme we would aim to bring them to the attention of the international community in industry and academia.
Motif 5 envisages three fluorines, one each on the three carbons of a cyclopropane ring, and with a stereochemistry that has all of the fluorines pointing up. This is claculated to be the most polar of the Motifs under investigation, and would be a special structure of interest to a wide range of scientists beyond bioactives research, including materials chemists and physicists, as it would have highly unusual polar properties.

Who will benefit from this research?
Organofluorine compounds make up 20% of all pharmaceuticals products internationally and 30% or all agrochemical products on the market. The organic materials industry relies very heavily on selectively fluorinated organic compounds and polymers. So innovation in the selective incorporation of fluorine contributes substantially to products that are designed to improve health, well being and the societal challenges of a growing population and developing third world sector (BRIC Nations). That is the global perspective of who will benefit from this research. More tangibly this research programme is focussed on the pharmaceuticals and agrochemicals sectors and also to organic materials industry (liquid crystals for displays). We will explore the introduction of a range of novel partially fluorinated motifs. One of the reasons to explore these partially fluorinated motifs is that they do not appear to increase the lipophilicity relative to common small hydrocarbon (-CH3, -OCH3) and fluorocarbon (eg -CF3 and -OCF3) attachments. The mixed nature of -H and -F provides polarity, which has a tendency to decreases their water solubility (LogP/D), relative to other common substituents. This is an attractive property which we believe merits investigation, and could provide significant benefit.

How will they benefit?
Companies involved in the discovery of new bioactive organic molecules will benefit by being able to utilise these new motifs in their own research programmes. They will hopefully be stimuated by the design concepts (mixed H/F motifs) and researchers in the area will be able to appliy or modify to their own purposes. Therefore the programme will stimulate thinking, and new approaches to current problems and challenges in drug and agrochemical discovery.
Tangentially, we will prepare liquid crystals with the mixed H/F motifs, to provide orientated polarity. In this case the fluorinated cyclopropanes provide polarity to a hydrocarbon molecule, in hydrocarbon matrices, a performance requirement in liquid crystal physics, such that molecules can be orientated and respond to changes in magnetic and electric fields.

The St Andrews lab has a continual ongoing dialogue (conferences, lectures, hosting visitors, collaborations) with relevant individuals in the chemical industry, who have interests in the chemistry, properties and performance of fluorine.

The PDRAs will develop synthesis skills and know how in organic fluorine chemistry and they will become specialists in understanding the specific effects of fluorine in terms of modulating properties (Dial a molecule; Grand Challenge).

St Andrews University is proactive in developing IP. This will be developed in consultation with Business Development Managers (BDMs) associated with Research Business Development & Contracts.

Beneficiaries within the wider public? Results from such a programme will be used in more general arenas for discussing the relevance of chemistry and molecular design behaviour and performance in the service of food security, health and communications (LC displays). This type of programme is particularly well suited to public interactions because it engages with these major societal concerns.

The research will be published and disseminated enthusiastically in leading journals and at appropriate international conferences.