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

J Enzyme Inhib Med Chem. 2014 Dec;29(6):840-5. doi: 10.3109/14756366.2013.858146. Epub 2014 Jan 14.

Abstract

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.

Keywords: Cytoprotection; NQO1; electrophilicity; sulfonamide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antioxidants / chemical synthesis*
  • Antioxidants / pharmacology
  • Binding Sites
  • Cell Line
  • Cytoskeletal Proteins / antagonists & inhibitors
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activators / chemical synthesis*
  • Enzyme Activators / pharmacology
  • Gene Expression Regulation
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Kelch-Like ECH-Associated Protein 1
  • Mice
  • Molecular Docking Simulation
  • NAD(P)H Dehydrogenase (Quinone) / chemistry*
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / agonists
  • NF-E2-Related Factor 2 / chemistry
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacology
  • Oxidation-Reduction
  • Protein Binding
  • Signal Transduction
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology

Substances

  • Adaptor Proteins, Signal Transducing
  • Antioxidants
  • Cytoskeletal Proteins
  • Enzyme Activators
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Nitriles
  • Sulfonamides
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse