Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 45, Issue 7, Pages 2957-2971Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2010.03.023
Keywords
Aurones; Chemoprevention; NAD(P)H:quinone oxidoreductase 1; Phase II enzyme inducers
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Funding
- National University of Singapore [R 148 000 084 112]
- Ministry of Education, Republic of Singapore
- National University of Singapore
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The chemopreventive potential of functionalized aurones and related compounds as inducers of NAD(P) H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) are described. Several 4,6-dimethoxy and 5-hydroxyaurones induced NQO1 activity of Hepa1c1c7 cells by 2-fold at submicromolar concentrations, making these the most potent inducers to be identified from this class. Mechanistically, induction of NQO1 was mediated by the activation of AhR/XRE and Nrf2/ARE pathways, indicating that aurones may be mixed activators of NQO1 induction or agents capable of exploiting the proposed cross-talk between the AhR and Nrf2 gene batteries. QSAR analysis by partial least squares projection to latent structures (PLS) identified size parameters, in particular those associated with non-polar surface areas, as an important determinant of induction activity. These were largely determined by the substitution on rings A and B. A stereoelectronic role for the exocyclic double bond as reflected in the E-LUMO term was also identified. The electrophilicity of the double bond or its effect on the conformation of the target compound are possible key features for induction activity. (c) 2010 Elsevier Masson SAS. All rights reserved.
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