Abstract
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.
Original language | English (US) |
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Pages (from-to) | 303-311 |
Number of pages | 9 |
Journal | ChemMedChem |
Volume | 13 |
Issue number | 4 |
DOIs | |
State | Published - Feb 20 2018 |
Bibliographical note
Publisher Copyright:© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Keywords
- Michael acceptors
- bis-electrophiles
- cysteine reactive
- helenalin
- p65/RelA transcription factor