Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs

Jeffries, Benjamin; Zhong, Wang; Felstead, Hannah R; Questel, Jean‐Yves Le; Scott, James S.; Chiarparin, Elisabetta; Graton, Jérôme; Linclau, Bruno

doi:10.1021/acs.jmedchem.9b01172

Cited by 106 publications

(103 citation statements)

References 106 publications

(294 reference statements)

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“…[11,12] On the other hand, the physical characteristics of perfluori-nated compounds are very different from those of the hydrogen-containing analogues. Most importantly, perfluorination simultaneously enhances hydrophobicity and lipophobicity, [13,14] a unique characteristic that creates exceptional biomedical possibilities. Although the number of pharmacologically applicable molecules containing perfluoroalkyl substituents is currently still limited, polyfluorinated compounds have shown promise in several areas of medicinal chemistry.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

et al. 2020

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The limited scope of antiviral drugs and increasing problem of antiviral drug resistance represent a global health threat. Glycopeptide antibiotics and their lipophilic derivatives have emerged as relevant inhibitors of diverse viruses. Herein, we describe a new strategy for the synthesis of dual hydrophobic and lipophobic derivatives of glycopeptides to produce selective antiviral agents without membrane‐disrupting activity. Perfluorobutyl and perfluorooctyl moieties were attached through linkers of different length to azido derivatives of vancomycin aglycone and teicoplanin pseudoaglycone, and the new derivatives were evaluated against a diverse panel of viruses. The teicoplanin derivatives displayed strong anti‐influenza virus activity at nontoxic concentrations. Some of the perfluoroalkylated glycopeptides were also active against a few other viruses such as herpes simplex virus or coronavirus. These data encourage further exploration of glycopeptide analogues for broad antiviral application.

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Section: Introductionmentioning

confidence: 99%

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

et al. 2020

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“…We have previously used the SMD implicit solvation model with the MN15 functional in theoretical lipophilicity predictions of linear fluorohydrins [27,28], which gave an excellent correlation with the experimental values (r 2 = 0.957), although the absolute values were much higher (a slope of >2 was obtained).…”

Section: Computational Resultsmentioning

confidence: 95%

“…Correlation of the DFT-calculated lipophilicities with the experimental values. A) fluorinated series D, E, F, G2-4, G7, G8, B)Compilation with other fluorohydrins (taken from reference[28]). …”

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confidence: 99%

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Jeffries¹,

Zhong²,

Troup³

et al. 2020

Beilstein J. Org. Chem.

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A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable, and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent.

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“…Indeed, this occurs experimentally. In fact, the lipophilicity contribution from the CF 3 group in 3 and 4 (Δlog P H/CF3 +0.7) is notably larger compared to an isolated CF 3 group in a hydrocarbon chain (Δlog P H/CF3 +0.3 – +0.4) [ 78 ]. In spite of this outcome, the model system seems too complex to be described by a single polarity parameter such as net dipole.…”

Section: Resultsmentioning

confidence: 99%

“…Discussions based on the net (molecular) dipole have become quite popular in the recent literature. Indeed, this parameter is critically relevant for the understanding of relatively small and simple molecular fragments [ 60 , 75 – 76 78 ], e.g., an axially rotating CF 3 group. Nonetheless, it is barely conclusive to approach interaction of complex molecules with solvents using net dipole alone.…”

Section: Resultsmentioning

confidence: 99%

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Kubyshkin¹

2020

Beilstein J. Org. Chem.

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Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of the interplay between the substituents and the main chain groups of the amino acid residue. This study aims to showcase the polarity-related effects that arise from the interaction between the functional groups in molecular models. Properties such as conformation, acid–base transition, and amide-bond isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pK a values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors C4-exo conformation of the pyrrolidine ring.

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Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs

Cited by 106 publications

References 106 publications

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

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