Modulation of the H-Bond Basicity of Functional Groups by α-Fluorine-Containing Functions and its Implications for Lipophilicity and Bioisosterism
Modulation of the H-bond basicity (pKHB) of various functional groups (FGs) by attaching fluorine functions and its impact on lipophilicity and bioisosterism considerations are described. In general, H/F replacement at the α-position to H-bond acceptors leads to a decrease of the pKHB value, resulting, in many cases, in a dramatic increase in the compounds' lipophilicity (log Po/w). In the case of α-CF2H, we found that these properties may also be affected by intramolecular H-bonds between CF2H and the FG. A computational study of ketone and sulfone series revealed that α-fluorination can significantly affect overall polarity, charge distribution, and conformational preference. The unique case of α-di- and trifluoromethyl ketones, which exist in octanol/water phases as ketone, hemiketal, and gem-diol forms, in equilibrium, prevents direct log Po/w determination by conventional methods, and therefore, the specific log Po/w values of these species were determined directly, for the first time, using Linclau's 19F NMR-based method.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:64 |
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| Enthalten in: |
Journal of medicinal chemistry - 64(2021), 8 vom: 22. Apr., Seite 4516-4531 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zafrani, Yossi [VerfasserIn] |
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| Links: |
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| Themen: |
284SYP0193 |
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| Anmerkungen: |
Date Completed 16.06.2021 Date Revised 16.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.0c01868 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM323995772 |
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| 500 | |a published: Print-Electronic | ||
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| 520 | |a Modulation of the H-bond basicity (pKHB) of various functional groups (FGs) by attaching fluorine functions and its impact on lipophilicity and bioisosterism considerations are described. In general, H/F replacement at the α-position to H-bond acceptors leads to a decrease of the pKHB value, resulting, in many cases, in a dramatic increase in the compounds' lipophilicity (log Po/w). In the case of α-CF2H, we found that these properties may also be affected by intramolecular H-bonds between CF2H and the FG. A computational study of ketone and sulfone series revealed that α-fluorination can significantly affect overall polarity, charge distribution, and conformational preference. The unique case of α-di- and trifluoromethyl ketones, which exist in octanol/water phases as ketone, hemiketal, and gem-diol forms, in equilibrium, prevents direct log Po/w determination by conventional methods, and therefore, the specific log Po/w values of these species were determined directly, for the first time, using Linclau's 19F NMR-based method | ||
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| 650 | 7 | |a Sulfones |2 NLM | |
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| 700 | 1 | |a Elias, Shlomi |e verfasserin |4 aut | |
| 700 | 1 | |a Pevzner, Alexander |e verfasserin |4 aut | |
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| 700 | 1 | |a Eichen, Yoav |e verfasserin |4 aut | |
| 700 | 1 | |a Saphier, Sigal |e verfasserin |4 aut | |
| 700 | 1 | |a Katalan, Shahaf |e verfasserin |4 aut | |
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