Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning

Abstract

Bioactive compounds generally need to cross membranes to arrive at their site of action. The octanol‐water partition coefficient (lipophilicity, logPOW) has proven to be an excellent proxy for membrane permeability. In modern drug discovery, logPOW 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 logPOW values with the corresponding membrane molar partitioning coefficients (logKp); 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.

Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous 1H NMR-Based logP/D Determination, Both Separately and in Mixtures

“…As mentioned above, Linclau’s NMR-based method for log P determination has been applied to fluorinated compounds using 19 F-NMR ,,,− or, as we have recently shown to phosphorus-containing compounds using 31 P NMR spectroscopy. However, at first glance, it seems that this method cannot be adapted to 1 H NMR for the vast majority of organic compounds that simply hold hydrogen atoms, due to the relatively narrow chemical shift range of this nucleus and the need for deuterated octanol.…”

Species-specific lipophilicities of fluorinated diketones in complex equilibria systems and their potential as multifaceted reversible covalent warheads

“…On the other hand the concentration of the hydrophilic form 1-T , which is mostly located in the aqueous phase, was reduced. It was very recently shown by Linclau’s group that lipophilicity modulations by fluorination correlate with membrane partitioning within families of fluorinated aliphatic compounds, using solid-state 19 F MAS NMR and standard lipid vesicles 41 . Similarly, we show here for the first time that a correlation may also be valid in complex equilibrium systems, an issue that is currently under investigation in our laboratory.…”

“…Artificial membranes (commercial) were composed of cellulose membrane and Lecithine (S-100). Water-liposomes mixtures were prepared using aqueous solutions of multi-lamellar lipid vesicles composed of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) as in Linclau’s recent publication 41 .…”

Conformational State of Fenamates at the Membrane Interface: A MAS NOESY Study

“…Probably due to the peculiarities of the chemical structure [ 17 ], FFA had its specifics of interaction with POPC; as a result, the changes in the three-dimensional structure observed were not characteristic for other the considered fenamates. As shown in a recent study [ 69 ], fluorinated fragments in the structure of the molecules of active pharmaceutical ingredients were decisive when changing the forms’ pharmaceutical and physical properties. The conformation distribution did not change much between DMSO- d 6 and POPC; this could have been due to other factors such as the size and shape of the FFA that allowed it to interact more strongly with the POPC molecules.…”