TY - JOUR
T1 - Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme
AU - Bensasson, René V.
AU - Dinkova-Kostova, Albena T.
AU - Zheng, Suqing
AU - Saito, Akira
AU - Li, Wei
AU - Zoete, Vincent
AU - Honda, Tadashi
N1 - Funding :Muséum National d'Histoire Naturelle; Stony Brook Foundation; Reata Pharmaceuticals Inc.; Solidar-Immun Foundation (C20953/A18644)
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Tricyclic, bicyclic, and monocyclic compounds containing cyanoenones induce various anti-inflammatory and cytoprotective enzymes through activation of the Keap1/Nrf2/ARE (antioxidant response element) pathway. The potency of these compounds as Nrf2 activators was determined using a prototypic cytoprotective enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The electron affinity (EA) of the compounds, expressed as the energy of their lowest unoccupied molecular orbital [E (LUMO)], was evaluated using two types of quantum mechanical calculations: the semiempirical (AM1) and the density functional theory (DFT) methods. We observed striking linear correlations [. r = 0.897 (AM1) and 0.936 (DFT)] between NQO1 inducer potency of these compounds and their E (LUMO) regardless of the molecule size. Importantly and interestingly, this finding demonstrates that the EA is the essentially important factor that determines the reactivity of the cyanoenones with Keap1.
AB - Tricyclic, bicyclic, and monocyclic compounds containing cyanoenones induce various anti-inflammatory and cytoprotective enzymes through activation of the Keap1/Nrf2/ARE (antioxidant response element) pathway. The potency of these compounds as Nrf2 activators was determined using a prototypic cytoprotective enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The electron affinity (EA) of the compounds, expressed as the energy of their lowest unoccupied molecular orbital [E (LUMO)], was evaluated using two types of quantum mechanical calculations: the semiempirical (AM1) and the density functional theory (DFT) methods. We observed striking linear correlations [. r = 0.897 (AM1) and 0.936 (DFT)] between NQO1 inducer potency of these compounds and their E (LUMO) regardless of the molecule size. Importantly and interestingly, this finding demonstrates that the EA is the essentially important factor that determines the reactivity of the cyanoenones with Keap1.
KW - Electron affinity
KW - Energy of the lowest unoccupied molecular orbital
KW - Keap1/Nrf2/ARE pathway
KW - NAD(P)H:quinone oxidoreductase 1 (NQO1) inducer
KW - Nrf2 activator
KW - QSAR
UR - http://www.scopus.com/inward/record.url?scp=84979272993&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2016.07.028
DO - 10.1016/j.bmcl.2016.07.028
M3 - Article
C2 - 27460172
AN - SCOPUS:84979272993
VL - 26
SP - 4345
EP - 4349
JO - Bioorganic & Medicinal Chemistry Letters
JF - Bioorganic & Medicinal Chemistry Letters
SN - 0960-894X
IS - 17
ER -