Investigating lipophilicity and hydrogen bonding properties of functionalised aliphatic compounds
Lead Research Organisation:
University of Southampton
Department Name: Sch of Chemistry
Abstract
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.
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.
Planned Impact
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.
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.
Publications
Jeffries B
(2018)
Reducing the Lipophilicity of Perfluoroalkyl Groups by CF2-F/CF2-Me or CF3/CH3 Exchange.
in Journal of medicinal chemistry
Linclau B
(2019)
A New Straightforward Method for Lipophilicity (log<em>P</em>) Measurement using <sup>19</sup>F NMR Spectroscopy
in Journal of Visualized Experiments
Linclau B
(2020)
Fluorinated carbohydrates as chemical probes for molecular recognition studies. Current status and perspectives.
in Chemical Society reviews
Jeffries B
(2020)
Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs.
in Journal of medicinal chemistry
Jeffries B
(2020)
Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups.
in Beilstein journal of organic chemistry
Linclau B
(2021)
Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery
in Angewandte Chemie
Linclau B
(2022)
Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery.
in Angewandte Chemie (International ed. in English)
Wang Z
(2023)
Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning.
in Angewandte Chemie (International ed. in English)
Wang Z
(2023)
Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning
in Angewandte Chemie
Description | We have explored a number of chemical modifications that medicinal chemists can use as part of the drug development process, especially towards optimising the physical properties of drug candidates. The focus has mainly been on optimising lipophilicity of compounds. Importantly, we have not only studied this using the conventional octanol solvent, but also using membranes. Finally, we have been able, for the first time, to measure lipophilicity of conformations of molecules. |
Exploitation Route | They may be used by pharmaceutical scientists, and by computational chemists |
Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |
Description | We have obtained an Impact Acceleration Award to investigate the commercialisation of a number of building blocks with fluorinated motifs. This has been successful, and compounds have been sent to a company. |
First Year Of Impact | 2022 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | ACS meeting San Francisco (online) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited Speaker at the American Chemical Society Meeting, San Francisco (USA), ("Lipophilicity modulations by aliphatic fluorination: an exploration") |
Year(s) Of Engagement Activity | 2021 |
Description | Accurate lipophilicity determination of fluorinated carbohydrates (poster RSC Carb) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | poster presentation Dr Zhong Want at RSC Carbohydrate Symposium, Warwick, 29-30/10/2016 |
Year(s) Of Engagement Activity | 2017 |
Description | An investigation on the effects of CF3/CH3 exchange in aliphatic and perfluoroalkylated alcohols on lipophilicity (poster RSC F) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Poster presentation of Benjamin Jeffries, 17th Annual RSC Fluorine Subject Group Postgraduate Meeting, 18-19th Sept, 2017, Leicester, 1st place award. |
Year(s) Of Engagement Activity | 2017 |
Description | BL Invited talk at Irish MedChem Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Speaker at 2nd Irish Medicinal Chemistry Symposium, Dublin (Ireland)("The influence of fluorination on lipophilicity and hydrogen bonding properties of aliphatic alcohols") |
Year(s) Of Engagement Activity | 2018 |
Description | BL Talk SCI |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited talk at SCI "Organofluorine Chemistry: synthetic methods and application" conference, London, UK ("The Influence of Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols") |
Year(s) Of Engagement Activity | 2018 |
Description | BL keynote at Oxford |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Keynote Speaker at 22st International Symposium on Fluorine Chemistry, Oxford (UK) ("Investigations on the lipophilicity of fluorinated aliphatic compounds") |
Year(s) Of Engagement Activity | 2018 |
Description | BL talk Galway |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk at University of Galway, Ireland ("Synthesis, properties, and biological activities of polyfluorinated carbohydrates") |
Year(s) Of Engagement Activity | 2018 |
Description | ESBOC-glycobiology, Gregynog |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invityed speaker at the annual ESBOC-glycobiology meeting, this time in Gregynog, "Exploring physical properties of carbohydrate derivatives: lipophilicities of fluorinated monosaccharides" |
Year(s) Of Engagement Activity | 2019 |
Description | GlycoBasque meeting March 19 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited speaker at the annual GlycoBasque meeting, CIC bioGUNE, Bilbao (Spain), "How fluorination modifies carbohydrate hydrogen bonding properties and lipophilicity" |
Year(s) Of Engagement Activity | 2019 |
Description | Presentation at CARBO XXXIV |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited presentation at the International Carbohydrate Conference CARBO - XXXIV, Lucknow (India), "Insights in carbohydrate lipophilicity" |
Year(s) Of Engagement Activity | 2019 |
Description | Presentation at EUROCARB |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Speaker at EUROCARB XX, Leiden (NL), "Lipophilicities of fluorinated carbohydrates and derivatives" |
Year(s) Of Engagement Activity | 2019 |
Description | Presentation at IITB |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited presentation at Institute of Indian Technology Bombay (IITB), Mumbai (India), "The Influence of Fluorination on Aliphatic Lipophilicity" |
Year(s) Of Engagement Activity | 2019 |
Description | The Influence of Aliphatic Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols (Syngenta Jealott's Hill) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Invited seminar at Syngenta (13/10/2017) |
Year(s) Of Engagement Activity | 2017 |
Description | The Influence of Aliphatic Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols and carbohydrates (Maynooth) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar at Maynooth University (06/06/2017) |
Year(s) Of Engagement Activity | 2017 |
Description | The Influence of Aliphatic Fluorination on Lipophilicity and Hydrogen Bond Properties of Alcohols: Application in Carbohydrates (Basel) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar at the Basler Chemische Gesellshaft |
Year(s) Of Engagement Activity | 2017 |
Description | The influence of aliphatic fluorination on lipophilicity and alcohol hydrogen bond properties (Sydney) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited Seminar, University of Sydney, 26/4/2017 |
Year(s) Of Engagement Activity | 2017 |
Description | The influence of aliphatic fluorination on lipophilicity and alcohol hydrogen bond properties (UNSW) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited seminar at The University of New South Wales, 02/05/2017 |
Year(s) Of Engagement Activity | 2017 |
Description | Zhong poster Oxford |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Poster: "Lipophilicity of Fluorinated Monosaccharides and Derivatives", 22nd International Symposium on Fluorine Chemistry, 22nd-27th July, 2018, Oxford |
Year(s) Of Engagement Activity | 2018 |