Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles

John C. Widen; Aaron M. Kempema; Jordan W. Baur; Hannah M Skopec; Jacob T. Edwards; Tenley J. Brown; Dennis A. Brown; Frederick A. Meece; Daniel A. Harki

doi:10.1002/cmdc.201700752

Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles

John C. Widen, Aaron M. Kempema, Jordan W. Baur, Hannah M Skopec, Jacob T. Edwards, Tenley J. Brown, Dennis A. Brown, Frederick A. Meece, Daniel A. Harki

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

21 Scopus citations

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)
Pages (from-to)	303-311
Number of pages	9
Journal	ChemMedChem
Volume	13
Issue number	4
DOIs	https://doi.org/10.1002/cmdc.201700752
State	Published - Feb 20 2018

Bibliographical note

Funding Information:
We gratefully acknowledge research funding from the US National Institutes of Health (NIH; R21-CA194661), The V Foundation for Cancer Research (V Scholar Award to D.A.H.), Hyundai Hope on Wheels (Hope Grant), University of Minnesota (UMN) Academic Health Center (Seed Grant no. 2010.01), UMN College of Pharmacy (Bighley Graduate Fellowship to J.C.W.; Melendy/Peters Summer Research Scholarship to H.M.S.), UMN Department of Chemistry (Heisig/Gleysteen Summer Undergraduate Research Fellowship awards to J.W.B. and J.T.E.), and the UMN Undergraduate Research Opportunities Program (awards to J.W.B., J.T.E., and T.J.B.). Mass spectrometry was performed at the Analytical Biochemistry Core Facility of the UMN Masonic Cancer Center, which is supported by the NIH (P30-CA77598 and S10RR-024618).

Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

Michael acceptors
bis-electrophiles
cysteine reactive
helenalin
p65/RelA transcription factor

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10.1002/cmdc.201700752

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894512

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title = "Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles",

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.",

keywords = "Michael acceptors, bis-electrophiles, cysteine reactive, helenalin, p65/RelA transcription factor",

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note = "Funding Information: We gratefully acknowledge research funding from the US National Institutes of Health (NIH; R21-CA194661), The V Foundation for Cancer Research (V Scholar Award to D.A.H.), Hyundai Hope on Wheels (Hope Grant), University of Minnesota (UMN) Academic Health Center (Seed Grant no. 2010.01), UMN College of Pharmacy (Bighley Graduate Fellowship to J.C.W.; Melendy/Peters Summer Research Scholarship to H.M.S.), UMN Department of Chemistry (Heisig/Gleysteen Summer Undergraduate Research Fellowship awards to J.W.B. and J.T.E.), and the UMN Undergraduate Research Opportunities Program (awards to J.W.B., J.T.E., and T.J.B.). Mass spectrometry was performed at the Analytical Biochemistry Core Facility of the UMN Masonic Cancer Center, which is supported by the NIH (P30-CA77598 and S10RR-024618). Publisher Copyright: {\textcopyright} 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

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AU - Skopec, Hannah M

AU - Edwards, Jacob T.

AU - Brown, Tenley J.

AU - Brown, Dennis A.

AU - Meece, Frederick A.

AU - Harki, Daniel A.

N1 - Funding Information: We gratefully acknowledge research funding from the US National Institutes of Health (NIH; R21-CA194661), The V Foundation for Cancer Research (V Scholar Award to D.A.H.), Hyundai Hope on Wheels (Hope Grant), University of Minnesota (UMN) Academic Health Center (Seed Grant no. 2010.01), UMN College of Pharmacy (Bighley Graduate Fellowship to J.C.W.; Melendy/Peters Summer Research Scholarship to H.M.S.), UMN Department of Chemistry (Heisig/Gleysteen Summer Undergraduate Research Fellowship awards to J.W.B. and J.T.E.), and the UMN Undergraduate Research Opportunities Program (awards to J.W.B., J.T.E., and T.J.B.). Mass spectrometry was performed at the Analytical Biochemistry Core Facility of the UMN Masonic Cancer Center, which is supported by the NIH (P30-CA77598 and S10RR-024618). Publisher Copyright: © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2018/2/20

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N2 - 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.

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KW - p65/RelA transcription factor

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Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles

Abstract

Bibliographical note

Keywords

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