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

Mostafa M. Ghorab (Lead / Corresponding author), Maureen Higgins, Mansour S. Alsaid, Reem K. Arafa, Abdelaaty A. Shahat, Albena T. Dinkova-Kostova

    Research output: Contribution to journalArticlepeer-review

    8 Citations (Scopus)

    Abstract

    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 1.6.99.2) 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.
    Original languageEnglish
    Pages (from-to)840-845
    Number of pages6
    JournalJournal of Enzyme Inhibition and Medicinal Chemistry
    Volume29
    Issue number6
    DOIs
    Publication statusPublished - Dec 2014

    Keywords

    • Cytoprotection
    • Electrophilicity
    • NQO1
    • Sulfonamide

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