TY - JOUR
T1 - Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84861494386&partnerID=8YFLogxK
U2 - 10.1021/jm3003922
DO - 10.1021/jm3003922
M3 - Article
C2 - 22533790
AN - SCOPUS:84861494386
SN - 0022-2623
VL - 55
SP - 4837
EP - 4846
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -