Functionalized aurones as inducers of NAD(P)H:quinone oxidoreductase 1 that activate AhR/XRE and Nrf2/ARE signaling pathways: synthesis, evaluation and SAR.
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.
Lee
Chong-Yew
CY
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Chew
Eng-Hui
EH
Go
Mei-Lin
ML
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D051379:Mice; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011808:Quinone Reductases / Q000096:biosynthesis*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects*; D015262:Xenobiotics / Q000378:metabolism
D000975:Antioxidants; D001572:Benzofurans; D051267:NF-E2-Related Factor 2; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; C486837:aurone; D019363:Cytochrome P-450 CYP1A1; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases