Synthesis, molecular modeling and NAD(P)H: quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides

Mostafa M. Ghorab, Maureen Higgins, Mansour S. Alsaid, Reem K. Arafa, Abdelaaty A. Shahat, Albena T. Dinkova-Kostova

Research output: Contribution to journalArticlepeer-review

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 (US)
Pages (from-to)840-845
Number of pages6
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume29
Issue number6
DOIs
StatePublished - Dec 1 2014

Keywords

  • Cytoprotection
  • Electrophilicity
  • NQO1
  • Sulfonamide

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Medicine(all)

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