Lipophilicity modulations by fluorination correlate with membrane partitioning
Lipophilicity modulations by fluorination correlate with membrane partitioning
Bioactive compounds generally need to cross membranes to arrive at their site of action. The octanol-water partition coefficient (lipophilicity, logP
OW) has proven to be an excellent proxy for membrane permeability. In modern drug discovery, logP
OW and bioactivity are optimized simultaneously, for which fluorination is one of the relevant strategies. The question arises as to which extent the often subtle logP modifications resulting from different aliphatic fluorine-motif introductions also lead to concomitant membrane permeability changes, given the difference in molecular environment between octanol and (anisotropic) membranes. It was found that for a given compound class, there is excellent correlation between logP
OW values with the corresponding membrane molar partitioning coefficients (logK
p); a study enabled by novel solid-state
19F NMR MAS methodology using lipid vesicles. Our results show that the factors that cause modulation of octanol-water partition coefficients similarly affect membrane permeability.
Aliphatic Compounds, Fluorination, Lipophilicity, Membrane Partitioning, NMR Spectroscopy
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Felstead, Hannah Rebecca
724886d1-059f-42b0-a44e-127e2115c376
Troup, Robert Ian
4e5eae00-ac0a-44a4-8c32-1042d6261c46
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Williamson, Philip
0b7715c6-b60e-4e95-a1b1-6afc8b9f372a
17 April 2023
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Felstead, Hannah Rebecca
724886d1-059f-42b0-a44e-127e2115c376
Troup, Robert Ian
4e5eae00-ac0a-44a4-8c32-1042d6261c46
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Williamson, Philip
0b7715c6-b60e-4e95-a1b1-6afc8b9f372a
Wang, Zhong, Felstead, Hannah Rebecca, Troup, Robert Ian, Linclau, Bruno and Williamson, Philip
(2023)
Lipophilicity modulations by fluorination correlate with membrane partitioning.
Angewandte Chemie International Edition, 62 (21), [e202301077].
(doi:10.1002/anie.202301077).
Abstract
Bioactive compounds generally need to cross membranes to arrive at their site of action. The octanol-water partition coefficient (lipophilicity, logP
OW) has proven to be an excellent proxy for membrane permeability. In modern drug discovery, logP
OW and bioactivity are optimized simultaneously, for which fluorination is one of the relevant strategies. The question arises as to which extent the often subtle logP modifications resulting from different aliphatic fluorine-motif introductions also lead to concomitant membrane permeability changes, given the difference in molecular environment between octanol and (anisotropic) membranes. It was found that for a given compound class, there is excellent correlation between logP
OW values with the corresponding membrane molar partitioning coefficients (logK
p); a study enabled by novel solid-state
19F NMR MAS methodology using lipid vesicles. Our results show that the factors that cause modulation of octanol-water partition coefficients similarly affect membrane permeability.
Text
Angew Chem Int Ed - 2023 - Wang - Lipophilicity modulations by fluorination correlate with membrane partitioning (1)
- Accepted Manuscript
Text
Linclau_Williamson manuscript
- Accepted Manuscript
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Linclau_Williamson supporting information
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Accepted/In Press date: 16 March 2023
e-pub ahead of print date: 17 April 2023
Published date: 17 April 2023
Additional Information:
Funding Information:
B.L. and P.T.F.W. are grateful to EPSRC for a project (EP/P019943/1) and core capability grant (EP/K039466/1). The UK 850 MHz solid‐state NMR Facility instruments used in this research were funded by EPSRC and BBSRC, as well as the University of Warwick, including via part funding through Birmingham Science City Advanced Materials Projects 1 and 2 supported by Advantage West Midlands (AWM) and the European Regional Development Fund (ERDF). We are grateful to Dr Dinu Iuga for his assistance with the collection of the F NMR data. B.L. acknowledges the Research Foundation Flanders (FWO, Belgium) for an Odysseus Type I grant (G0F5621N). 19
Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
Keywords:
Aliphatic Compounds, Fluorination, Lipophilicity, Membrane Partitioning, NMR Spectroscopy
Identifiers
Local EPrints ID: 476176
URI: http://eprints.soton.ac.uk/id/eprint/476176
ISSN: 1433-7851
PURE UUID: 826fec17-523a-4d6e-aa6f-28cffcbe8bcf
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Date deposited: 13 Apr 2023 16:42
Last modified: 17 Mar 2024 03:09
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Author:
Hannah Rebecca Felstead
Author:
Robert Ian Troup
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