Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents. / Zheng, Suqing; Laxmi, Y. R. Santosh; 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 journal › Article
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TY - JOUR
T1 - Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents
A1 - Zheng,Suqing
A1 - Laxmi,Y. R. Santosh
A1 - David,Emilie
A1 - Dinkova-Kostova,Albena T.
A1 - Shiavoni,Katherine H.
A1 - Ren,Yanqing
A1 - Zheng,Ying
A1 - Trevino,Isaac
A1 - Bumeister,Ronald
A1 - Ojima,Iwao
A1 - Wigley,W. Christian
A1 - Bliska,James B.
A1 - Mierke,Dale F.
A1 - Honda,Tadashi
AU - Zheng,Suqing
AU - Laxmi,Y. R. Santosh
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-alpha and IL-1 beta with potencies that are higher than those of bardoxolone methyl and TBE-31.</p>
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-alpha and IL-1 beta with potencies that are higher than those of bardoxolone methyl and TBE-31.</p>
U2 - 10.1021/jm3003922
DO - 10.1021/jm3003922
M1 - Article
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
VL - 55
SP - 4837
EP - 4846
ER -