The Reactivity of α-Fluorinated Mono- and Diketones Uncovers their Potential as Electrophilic Warheads for Reversible Covalent Drugs

Yossi Zafrani; Ido Michael Herzog; Eliav Blum; Shlomi Elias; Sigal Saphier; Ishay Columbus

doi:10.1002/ejoc.202500380

The Reactivity of α-Fluorinated Mono- and Diketones Uncovers their Potential as Electrophilic Warheads for Reversible Covalent Drugs

Yossi Zafrani
, Ido Michael Herzog
, Eliav Blum
, Shlomi Elias
, Sigal Saphier
, Ishay Columbus

Israel Institute for Biological Research

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Fluorinated diketones (FDKs) are electrophilic moieties holding unique molecular properties that make them potential reversible and multifaceted covalent warheads for drug design. To further explore this potential, the multicomponent equilibrium systems of various fluorinated monoketones (FMKs) and FDKs in the presence of the relevant nucleophilic amino acids serine, cysteine, and lysine are studied. These equilibrium systems are investigated using ¹⁹ F- and ¹³C- NMR spectroscopy, and reveal that for both cysteine and lysine most of the FMKs and FDKs studied may potentially serve as electrophilic warheads for reversible covalent drugs.

Original language	English
Article number	e202500380
Journal	European Journal of Organic Chemistry
Volume	28
Issue number	35
DOIs	https://doi.org/10.1002/ejoc.202500380
State	Published - 26 Sep 2025
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). European Journal of Organic Chemistry published by Wiley-VCH GmbH.

Keywords

electrophilic warheads
fluorinated ketones
nucleophilic amino acids
reaction equilibrium
reversible covalent drugs

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10.1002/ejoc.202500380

Cite this

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abstract = "Fluorinated diketones (FDKs) are electrophilic moieties holding unique molecular properties that make them potential reversible and multifaceted covalent warheads for drug design. To further explore this potential, the multicomponent equilibrium systems of various fluorinated monoketones (FMKs) and FDKs in the presence of the relevant nucleophilic amino acids serine, cysteine, and lysine are studied. These equilibrium systems are investigated using 19 F- and 13C- NMR spectroscopy, and reveal that for both cysteine and lysine most of the FMKs and FDKs studied may potentially serve as electrophilic warheads for reversible covalent drugs.",

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T1 - The Reactivity of α-Fluorinated Mono- and Diketones Uncovers their Potential as Electrophilic Warheads for Reversible Covalent Drugs

AU - Zafrani, Yossi

AU - Herzog, Ido Michael

AU - Blum, Eliav

AU - Elias, Shlomi

AU - Saphier, Sigal

AU - Columbus, Ishay

PY - 2025/9/26

Y1 - 2025/9/26

N2 - Fluorinated diketones (FDKs) are electrophilic moieties holding unique molecular properties that make them potential reversible and multifaceted covalent warheads for drug design. To further explore this potential, the multicomponent equilibrium systems of various fluorinated monoketones (FMKs) and FDKs in the presence of the relevant nucleophilic amino acids serine, cysteine, and lysine are studied. These equilibrium systems are investigated using 19 F- and 13C- NMR spectroscopy, and reveal that for both cysteine and lysine most of the FMKs and FDKs studied may potentially serve as electrophilic warheads for reversible covalent drugs.

AB - Fluorinated diketones (FDKs) are electrophilic moieties holding unique molecular properties that make them potential reversible and multifaceted covalent warheads for drug design. To further explore this potential, the multicomponent equilibrium systems of various fluorinated monoketones (FMKs) and FDKs in the presence of the relevant nucleophilic amino acids serine, cysteine, and lysine are studied. These equilibrium systems are investigated using 19 F- and 13C- NMR spectroscopy, and reveal that for both cysteine and lysine most of the FMKs and FDKs studied may potentially serve as electrophilic warheads for reversible covalent drugs.

KW - electrophilic warheads

KW - fluorinated ketones

KW - nucleophilic amino acids

KW - reaction equilibrium

KW - reversible covalent drugs

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The Reactivity of α-Fluorinated Mono- and Diketones Uncovers their Potential as Electrophilic Warheads for Reversible Covalent Drugs

Abstract

Bibliographical note

Keywords

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