title: Synthesis, structure, and glutathione peroxidase-like activity of amino acid containing ebselen analogues and diaryl diselenides.
abstract: The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, India.
authors.forename: Karuthapandi
authors.initials: K
authors.lastname: Selvakumar
authors.forename: Poonam
authors.initials: P
authors.lastname: Shah
authors.forename: Harkesh B
authors.initials: HB
authors.lastname: Singh
authors.forename: Ray J
authors.initials: RJ
authors.lastname: Butcher
mesh_terms: D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics; D005979:Glutathione Peroxidase / Q000378:metabolism*; D054833:Isoindoles; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D005979:Glutathione Peroxidase; D005978:Glutathione