title: Synthesis, molecular modeling and NAD(P)H:quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides.
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
  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.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, King Saud University , Riyadh , Kingdom of Saudi Arabia .
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Ghorab
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.forename: Mansour S
authors.initials: MS
authors.lastname: Alsaid
authors.forename: Reem K
authors.initials: RK
authors.lastname: Arafa
authors.forename: Abdelaaty A
authors.initials: AA
authors.lastname: Shahat
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D062105:Molecular Docking Simulation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011485:Protein Binding; D015398:Signal Transduction; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D003598:Cytoskeletal Proteins; D020536:Enzyme Activators; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009570:Nitriles; D013449:Sulfonamides; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse
keywords: Cytoprotection; NQO1; electrophilicity; sulfonamide