title: 1,1,2-Tris-organoselenide alkene derivatives, but not 1,2-bis-organoselenide alkene derivatives, inhibited delta-aminolevulinate dehydratase activity from human erythrocytic cells in vitro.
abstract: Organochalcogens are important intermediates and useful reagents in organic synthesis. Recent data from our laboratory demonstrated that bis and tris-selenide alkene derivatives are attractive synthetic targets because of their chemio-, regio- and stereo-selective reactions. Since the erythrocytic delta-aminolevulinate dehydratase (delta-ALA-D) activity could be an important indicator of toxicity, this report investigated bis and tris-selenide alkene derivatives effects on blood delta-ALA-D in vitro. To investigate the mechanisms by which these compounds inhibit human blood delta-ALA-D activity, a thiol reducing agent or zinc chloride were used. 1,2-Bis-selenide alkene derivatives 1a (R=4-MeOC(6)H(4)), 1b (R=4-ClC(6)H(4)) and 1c (R=2,4,6-Me(3)C(6)H(2)) did not inhibit human blood delta-ALA-D activity. 1,1,2-Tris-selenide alkene derivative 2a (R=C(6)H(5)) was the most potent delta-ALA-D inhibitor. Compounds 2b (R=4-MeOC(6)H(4)) and 2c (R=4-ClC(6)H(4)) displayed similar inhibitory potency towards delta-ALA-D activity. Dithiothreitol, a hydrophobic SH-reducing agent, was able to restore and to protect delta-ALA-D activity inhibited by tris-selenide alkene derivatives. Conversely, ZnCl(2) did not alter the enzyme inhibition induced by tris-selenide alkene derivatives. From these findings we suggest that 1,1,2-tris-selenide alkene derivatives inhibited delta-ALA-D activity by an interaction with essential sulfhydryl groups for the enzyme activity.
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação, Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Borges
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dadalt
authors.forename: Lucielli
authors.initials: L
authors.lastname: Savegnago
authors.forename: Angélica V
authors.initials: AV
authors.lastname: Moro
authors.forename: Joao B T
authors.initials: JB
authors.lastname: Rocha
authors.forename: Cristina W
authors.initials: CW
authors.lastname: Nogueira
mesh_terms: D000475:Alkenes / Q000633:toxicity; D002712:Chlorides / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D016566:Organoselenium Compounds / Q000633:toxicity*; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D000475:Alkenes; D002712:Chlorides; D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D017967:Zinc Compounds; C016837:zinc chloride; D000623:Porphobilinogen Synthase; D004229:Dithiothreitol