In biological systems, the Keap1/Nrf2/antioxidant response element pathway determines the ability of mammalian cells to adapt and survive conditions of oxidative, electrophilic and inflammatory stress by regulating the production of cytoprotective enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1, EC 220.127.116.11) being one of them. Novel biologically active benzenesulfonamides 2, 3, 5-7, penta-2,4-dienamide 4 and chromene-2-carboxamide 8 structurally augmented with an electron-deficient Michael acceptor enone or cyanoenone functionalities were prepared. A new biological activity was conferred to these molecules, that of induction of NQO1. The potency of induction was increased by incorporation of a nitrile group adjacent to the enone and the dinitrophenyl derivative 3 was the most promising inducer. Also, molecular docking of the new compounds in the Nrf2-binding site of Keap1 was performed to assess their ability to inhibit Keap1 which biologically leads to a consequent Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed considerable interactions between the new molecules and essential binding site amino acids.
|Number of pages||6|
|Journal||Journal of Enzyme Inhibition and Medicinal Chemistry|
|Publication status||Published - Dec 2014|
Ghorab, M. M., Higgins, M., Alsaid, M. S., Arafa, R. K., Shahat, A. A., & Dinkova-Kostova, A. T. (2014). Synthesis, molecular modeling and NAD(P)H:quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides: quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides. Journal of Enzyme Inhibition and Medicinal Chemistry, 29(6), 840-845. https://doi.org/10.3109/14756366.2013.858146