Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning

Area of Science:

• Medicinal Chemistry
• Biophysics
• Analytical Chemistry

Background:

• Bioactive compounds require membrane transport for efficacy.
• Lipophilicity, quantified by octanol-water partition coefficient (logP_OW), is a key predictor of membrane permeability.
• Fluorination is a common strategy in drug discovery to optimize lipophilicity and bioactivity.

Purpose of the Study:

• To investigate if subtle logP_OW changes from aliphatic fluorination correlate with membrane permeability.
• To assess the validity of logP_OW as a proxy for membrane partitioning in the context of fluorinated compounds.
• To explore the relationship between lipophilicity and membrane permeability using advanced NMR techniques.

Main Methods:

• Utilized novel solid-state ¹⁹ F NMR MAS (Magic Angle Spinning) methodology.
• Employed lipid vesicles to model biological membranes.
• Measured membrane molar partitioning coefficients (logK_p) and compared them with logP_OW values.

Main Results:

• Demonstrated an excellent correlation between logP_OW and logK_p for a given compound class.
• Confirmed that factors modulating octanol-water partition coefficients similarly affect membrane permeability.
• Validated the predictive power of logP_OW for membrane transport of fluorinated compounds.

Conclusions:

• Subtle modifications in lipophilicity through aliphatic fluorination directly impact membrane permeability.
• The octanol-water partition coefficient remains a reliable indicator of membrane partitioning, even with nuanced structural changes.
• This study validates established principles while introducing advanced methods for precise assessment in drug design.