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Helenalin Analogues Targeting NF‐κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles
Author(s) -
Widen John C.,
Kempema Aaron M.,
Baur Jordan W.,
Skopec Hannah M.,
Edwards Jacob T.,
Brown Tenley J.,
Brown Dennis A.,
Meece Frederick A.,
Harki Daniel A.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700752
Subject(s) - electrophile , chemistry , stereochemistry , thiol , potency , methylene , natural product , biochemistry , in vitro , medicinal chemistry , catalysis
Helenalin is a pseudoguaianolide natural product that targets Cys38 within the DNA binding domain of NF‐κB transcription factor p65 (RelA). Helenalin contains two Michael acceptors that covalently modify cysteines: a α‐methylene‐γ‐butyrolactone and a cyclopentenone. We recently reported two simplified helenalin analogues that mimic the biological activity of helenalin and contain both electrophilic moieties. To determine the individual contributions of the Michael acceptors toward NF‐κB inhibition, we synthesized a small library of helenalin‐based analogues containing various combinations of α‐methylene‐γ‐butyrolactones and cyclopentenones. The kinetics of thiol addition to a subset of the analogues was measured to determine the relative thiol reactivities of the embedded electrophiles. Additionally, the cellular NF‐κB inhibitory activities of the analogues were determined to elucidate the contributions of each Michael acceptor to biological potency. Our studies suggest the α‐methylene‐γ‐butyrolactone contributes most significantly to the NF‐κB inhibition of our simplified helenalin analogues.