TY - JOUR
T1 - Species-specific lipophilicities of fluorinated diketones in complex equilibria systems and their potential as multifaceted reversible covalent warheads
AU - Columbus, Ishay
AU - Ghindes-Azaria, Lee
AU - Herzog, Ido Michael
AU - Blum, Eliav
AU - Parvari, Galit
AU - Eichen, Yoav
AU - Cohen, Yoram
AU - Gershonov, Eytan
AU - Drug, Eyal
AU - Saphier, Sigal
AU - Elias, Shlomi
AU - Smolkin, Boris
AU - Zafrani, Yossi
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/9/15
Y1 - 2023/9/15
N2 - Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF2(CO)2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF2(CO)2 warheads toward cysteine residues.
AB - Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF2(CO)2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF2(CO)2 warheads toward cysteine residues.
UR - http://www.scopus.com/inward/record.url?scp=85171681672&partnerID=8YFLogxK
U2 - 10.1038/s42004-023-01004-2
DO - 10.1038/s42004-023-01004-2
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C2 - 37715018
AN - SCOPUS:85171681672
SN - 2399-3669
VL - 6
JO - Communications Chemistry
JF - Communications Chemistry
IS - 1
M1 - 197
ER -