Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme.

Abstract

UNLABELLED:

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.

• Authors: René V Bensasson, Albena T Dinkova-Kostova, Suqing Zheng, Akira Saito, Wei Li, Vincent Zoete, Tadashi Honda
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 17 Pg. 4345-9 (09 01 2016) ISSN: 1464-3405 [Electronic] England
• PMID: 27460172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Alkenes
• Kelch-Like ECH-Associated Protein 1
• Ketones
• Nitriles
• Sulfhydryl Compounds
• cyanoethenethiol
• NAD(P)H Dehydrogenase (Quinone)

Topics

• Alkenes (chemistry)
• Animals
• Cell Line, Tumor
• Cyclization
• Cytoprotection
• Electrons
• Enzyme Induction (drug effects)
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Ketones (chemistry)
• Mice
• Molecular Structure
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• Nitriles (chemistry, pharmacology)
• Quantum Theory
• Signal Transduction (drug effects)
• Sulfhydryl Compounds (chemistry, pharmacology)