Synthesis, chemical reactivity as michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents(1)

Suqing Zheng, Y. R. Santosh Laxmi, Emilie David, Albena T. Dinkova-Kostova, Katherine H. Shiavoni, Yanqing Ren, Ying Zheng, Isaac Trevino, Ronald Bumeister, Iwao Ojima, W. Christian Wigley, James B. Bliska, Dale F. Mierke, Tadashi Honda

Research output: Contribution to journalArticle

Abstract

Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.

Original languageEnglish (US)
Pages (from-to)4837-4846
Number of pages10
JournalJournal of Medicinal Chemistry
Volume55
Issue number10
DOIs
StatePublished - May 24 2012

Fingerprint

Anti-Inflammatory Agents
Phase III Clinical Trials
Interleukin-1
Sulfhydryl Compounds
Biological Assay
Macrophages
Apoptosis
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
TBE 31

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis, chemical reactivity as michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents(1). / Zheng, Suqing; Santosh Laxmi, Y. R.; David, Emilie; Dinkova-Kostova, Albena T.; Shiavoni, Katherine H.; Ren, Yanqing; Zheng, Ying; Trevino, Isaac; Bumeister, Ronald; Ojima, Iwao; Wigley, W. Christian; Bliska, James B.; Mierke, Dale F.; Honda, Tadashi.

In: Journal of Medicinal Chemistry, Vol. 55, No. 10, 24.05.2012, p. 4837-4846.

Research output: Contribution to journalArticle

Zheng, S, Santosh Laxmi, YR, David, E, Dinkova-Kostova, AT, Shiavoni, KH, Ren, Y, Zheng, Y, Trevino, I, Bumeister, R, Ojima, I, Wigley, WC, Bliska, JB, Mierke, DF & Honda, T 2012, 'Synthesis, chemical reactivity as michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents(1)', Journal of Medicinal Chemistry, vol. 55, no. 10, pp. 4837-4846. https://doi.org/10.1021/jm3003922
Zheng, Suqing ; Santosh Laxmi, Y. R. ; David, Emilie ; Dinkova-Kostova, Albena T. ; Shiavoni, Katherine H. ; Ren, Yanqing ; Zheng, Ying ; Trevino, Isaac ; Bumeister, Ronald ; Ojima, Iwao ; Wigley, W. Christian ; Bliska, James B. ; Mierke, Dale F. ; Honda, Tadashi. / Synthesis, chemical reactivity as michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents(1). In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 10. pp. 4837-4846.
@article{d62cd1a5798c4660beb8c09b9756f23c,
title = "Synthesis, chemical reactivity as michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents(1)",
abstract = "Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.",
author = "Suqing Zheng and {Santosh Laxmi}, {Y. R.} and Emilie David and Dinkova-Kostova, {Albena T.} and Shiavoni, {Katherine H.} and Yanqing Ren and Ying Zheng and Isaac Trevino and Ronald Bumeister and Iwao Ojima and Wigley, {W. Christian} and Bliska, {James B.} and Mierke, {Dale F.} and Tadashi Honda",
year = "2012",
month = "5",
day = "24",
doi = "10.1021/jm3003922",
language = "English (US)",
volume = "55",
pages = "4837--4846",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Synthesis, chemical reactivity as michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents(1)

AU - Zheng, Suqing

AU - Santosh Laxmi, Y. R.

AU - David, Emilie

AU - Dinkova-Kostova, Albena T.

AU - Shiavoni, Katherine H.

AU - Ren, Yanqing

AU - Zheng, Ying

AU - Trevino, Isaac

AU - Bumeister, Ronald

AU - Ojima, Iwao

AU - Wigley, W. Christian

AU - Bliska, James B.

AU - Mierke, Dale F.

AU - Honda, Tadashi

PY - 2012/5/24

Y1 - 2012/5/24

N2 - Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.

AB - Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.

UR - http://www.scopus.com/inward/record.url?scp=84861494386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861494386&partnerID=8YFLogxK

U2 - 10.1021/jm3003922

DO - 10.1021/jm3003922

M3 - Article

C2 - 22533790

AN - SCOPUS:84861494386

VL - 55

SP - 4837

EP - 4846

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 10

ER -