Diselenoamino acid derivatives as GPx mimics and as substrates of TrxR: in vitro and in silico studies.

Excessive production of reactive species in living cells usually has pathological effects. Consequently, the synthesis of compounds which can mimic the activity of antioxidant enzymes has inspired great interest. In this study, a variety of diselenoamino acid derivatives from phenylalanine and valine were tested to determine whether they could be functional mimics of glutathione peroxidase (GPx) and substrates for liver thioredoxin reductase (TrxR). Diselenides C and D showed the best GPx mimicking properties when compared with A and B. We suppose that the catalytic activity of diselenide GPx mimics depends on the steric effects, which can be influenced by the number of carbon atoms between the selenium atom and the amino acid residue and/or by the amino acid lateral residue. Compounds C and D stimulated NADPH oxidation in the presence of partially purified hepatic mammalian TrxR, indicating that they are substrates for TrxR. Our study indicates a possible dissociation between the two pathways for peroxide degradation (i.e., via a substrate for TrxR or via mimicry of GPx) for compounds tested in this study, except for PhSeSePh, and the antioxidant activity of diselenoamino acids can also be attributed to their capacity to mimic GPx and to be a substrate for mammalian TrxR.

Selenothymidine protects against biochemical and behavioral alterations induced by ICV-STZ model of dementia in mice.

The present study evaluated the neuroprotective effects of one selenium-containing AZT derivative compound (S1073) in memory and learning impairment caused by Intracerebroventricular-streptozotocin (ICV-STZ). ICV-STZ in mice causes impairment of energy metabolism with oxidative damage and cholinergic dysfunction, and provides a relevant model for sporadic dementia of Alzheimer's type (AD). Acetylcolinesterase (AChE), Catalase (CAT), dichlorofluorescein oxidation (DCFH), TBARS and thiol content were measured. Swiss adult mice were pre-treated with S1073 [1 mmol/kg] (i.p.) and after 30 min of the injection received a bilateral dose of STZ [11.3 µmol/l]. After 8 days' STZ injection, we performed the behavioral experiments (Beaker test, Open field and Morris water maze task). ICV-STZ caused significant learning and memory impairments, which were significantly improved by S1073 pre-treatment. A significant increase in cerebral DFCH, TBARS levels and AChE activity and a disturbance in the memory and learning were observed in ICV-STZ injected animals. S1073 significantly ameliorated all alterations induced by ICV-STZ in mice. All these findings support the neuroprotective role of S1073 in mice model of Alzheimer's dementia-type induced by ICV-STZ, which may be associated with its antioxidant activity and/or with its inhibitory effect in brain AChE. In fact, in silico analysis indicated that S1073 may be an inhibitor of AChE.

4-Organoseleno-Isoquinolines Selectively and Reversibly Inhibit the Cerebral Monoamine Oxidase B Activity.

Isoquinolines are formed endogenously as metabolites of neurotransmitters and are studied because they have structures similar to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and selegiline, a selective inhibitor of MAO-B. This study investigated a possible in vitro inhibitory activity of new 4-organochalcogen-isoquinoline derivatives, containing sulfur 1, selenium 2 or tellurium 3 on MAO-A and B activities. Considering that the non-substituted selenoisoquinoline derivative 2 showed the best inhibitory profile (IC50 = 36.45 µM), new compounds were synthesized by adding substituents (methyl 2a, fluorine 2b, chloro 2c and trifluoromethyl 2d) to the aromatic ring bonded to the selenium atom of compound 2. All tested compounds were selective MAO-B inhibitors, although only the substituted isoquinoline derivative 2b showed IC50 lower than the concentration of 100 µM (IC50 = 82.41 µM). Compounds 2 and 2b were chosen to study the inhibitory profile. These compounds demonstrated reversible and mixed inhibition by decreasing apparent V (app) max and increasing apparent K (app) m, however the non-substituted compound 2 was a more potent inhibitor than the substituted compound 2b (K i = 7.07 and 16.30 µM). In conclusion, selenoisoquinolines 2 and 2b fit in the profile of third generation MAO inhibitors (selective and reversible), which are promising alternatives for treatment of emotional and neurodegenerative disorders.