André L. Stein

Copper iodide-catalyzed cyclization of (Z)-chalcogenoenynes.

We present here our results of the efficient copper-catalyzed cyclizations of chalcogenoenynes and establish a route to obtain 3-substituted chalcogenophenes in good to excellent yields. In addition, the obtained chalcogenophenes were readily transformed to more complex products using the palladium-catalyzed cross-coupling reactions with boronic acids to give Suzuki-type products in good yields.

Antidepressant-like pharmacological profile of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene: Involvement of serotonergic system

This study evaluated the effect of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene (DPS) in the mouse forced swim test (FST) and tail suspension test (TST), two assays predictive of depressant activity. The involvement of serotonergic system in the effect caused by DPS was studied. The antidepressant-like effect of combined treatment with subeffetive doses of DPS and paroxetine, a selective serotonin reuptake inhibitor (SSRI) was investigated. Further, we verified the possible mechanism responsible for antidepressive-like effect of DPS. The results show that DPS (50 and 100 mg/kg, p.o.) significantly reduced the immobility time during the FST and TST, without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of DPS (50 mg/kg, p.o.) in the FST was prevented by pretreatment of mice with pCPA (100 mg/kg, i.p., once a day for 4 consecutive days, an inhibitor of 5-HT synthesis), WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptor antagonist), ritanserin (1 mg/kg, i.p., a 5-HT2 receptor antagonist) or ondansetron (1 mg/kg, i.p., a 5-HT3 receptor antagonist). Combined treatment with paroxetine and DPS reduced the immobility time in the FST. DPS at the doses of 10-100 mg/kg did not produce any change in the cerebral activity of MAO-A or MAO-B. DPS at the dose of 50 mg/kg inhibited significantly 5-HT uptake in synaptosomes. These results suggest that DPS produced an antidepressant-like effect in the mouse FST and TST and this effect seems most likely to be mediated through an interaction with serotonergic system, particularly by 5-HT reuptake inhibition.

Application of Copper(I) Iodide/Diorganoyl Dichalcogenides to the Synthesis of 4‐Organochalcogen Isoquinolines by Regioselective CN and CChalcogen Bond Formation

A copper-catalyzed cyclization of (ortho-alkynyl)benzaldimines with diorganoyl dichalcogenides allowed the synthesis of 4-organochalcogen isoquinolines, whereas the presence of base in the reaction medium inhibited the product formation producing the undesirable isoquinoline without the organochalcogen atom at the 4-position. The cyclization reaction was carried out by using CuI (20 %) as a catalyst with diorganoyl dichalcogenides (1.5 equiv) in the presence of DMF at 100 °C. Furthermore, the reaction did not require an argon atmosphere and was carried out in an open flask. The cyclization reaction tolerated a variety of functional groups both in ortho-alkynylbenzaldimines and diorganoyl dichalcogenides, such as trifluoromethyl, chloro, fluorine, and methoxyl, to give the six-membered heterocyclic ring exclusively through a 6-endo-dig cyclization process. The organochalcogen group present at the 4-position of the isoquinoline ring was further subjected to a selective chalcogen-lithium exchange reaction followed by the addition of aldehydes to afford the desired secondary alcohols in good yields. The obtained isoquinolines also proved to be suitable substrates for the Suzuki and Sonogashira coupling conditions affording the corresponding products through C-C bond formation.

ERK1/2 phosphorylation is involved in the antidepressant-like action of 2,5-diphenyl-3-(4-fluorophenylseleno)-selenophene in mice

We investigated the antidepressant-like action of 5 compounds belonging to the selenophene class. The involvement of ERK and CREB activation in this action was also demonstrated. In the experiment 1, time-course and dose-response effect of H-DPS, CH3-DPS, Cl-DPS, F-DPS and CF3-DPS were accompanied in the mouse forced swimming test (FST). Firstly, animals received compounds at a dose of 50mg/kg, by intragastric (i.g.) route, at different times (15-240 min) before test. Results showed that the peak of maximum anti-despair behavior induced by Cl-DPS, F-DPS and CF3-DPS was at 30 min; maximum effect of H-DPS and CH3-DPS was found at 60 min, which was maintained until 120 min. Regarding dose-response effect, all compounds reduced immobility time and increased latency for the first episode of immobility at a dose of 50mg/kg. In addition, F-DPS also showed antidepressant-like action at a dose of 25mg/kg, whilst H-DPS, CH3-DPS, Cl-DPS and CF3-DPS were not effective at lower doses. Thus, F-DPS was chosen for further investigation of its mechanism of action. Experiment 2 showed that treatment of animals with F-DPS (50 mg/kg, i.g.) significantly increased phosphorylated ERK1/2 levels in the prefrontal cortex and hippocampus; however, pCREB levels were not affected. Additionally, in the experiment 3 anti-immobility effect of F-DPS was completely blocked by pretreatment of animals with PD 98,059, an inhibitor of ERK phosphorylation, suggesting that ERK signalling activation is involved in its antidepressant-like action in mice. Together our data appoint F-DPS as a promising molecule for the development of a new antidepressant therapy.

Antioxidant effect of quinoline derivatives containing or not selenium: Relationship with antinociceptive action quinolines are antioxidant and antinociceptive

The present study investigated the antioxidant effect of a new class of quinoline derivatives (a-d) on assays in vitro. Lipid peroxidation, thiol peroxidase-like and free radical scavenging activities were determined to evaluate antioxidant activity of compounds. Thiol oxidase-like and δ-aminolevulinate dehydratase activities were performed as a toxicological parameter. A second objective of this study was to evaluate the in vivo antinociceptive effect of the compound with better antioxidant effect and without toxic effects in a model of nociception induced by formalin in mice. In liver, at 100 µM, compound a reduced the lipid peroxidation to the control levels, while compounds c and d partially reduced it. In brain, only compound d partially reduced the lipid peroxidation at 50 and 100 µM. Compound b did not have an effect on the lipid peroxidation. Thiol peroxidase-like and free radical scavenging activities are not involved in the antioxidant mechanisms of these compounds. Compounds did not present thiol oxidase-like activity and effect on the δ-aminolevulinate dehydratase. In vivo experiments showed that compound a caused an inhibition of licking time in the first and second phases, and edema formation induced by formalin. In conclusion, quinoline derivative without selenium presented better in vitro antioxidant effect and in vivo antinociceptive activity.

Sulfhydryl‐Based Inhibition of δ‐ALA‐D and Na+, K+‐ATPase Activities Depends on the Organoselenium Group Bonded to the Isoquinoline

Organoselenium compounds and isoquinoline derivatives have their toxicity linked to induction of pro‐oxidant situations. δ‐Aminolevulinate dehydratase (δ‐ALA‐D) and Na+, K+‐ATPase have sulfhydryl groups susceptible to oxidation. Thus, we investigated toxicological effects of 4‐organoseleno‐isoquinoline derivatives, cerebral monoamine oxidase B inhibitors, on rat cerebral δ‐ALA‐D and Na+, K+‐ATPase activities and the involvement of sulfhydryl groups in vitro. Compounds substituted with fluoro (4‐(4‐fluorophenylseleno)‐3‐phenylisoquinoline), chloro (4‐(4‐chlorophenylseleno)‐3‐phenylisoquinoline) and trifluoro (4‐(3‐trifluoromethylphenylseleno)‐3‐phenylisoquinoline) at the selenium‐bonded aromatic ring inhibited δ‐ALA‐D (IC50 values: 78.42, 92.27, 44.98 µM) and Na+, K+‐ATPase (IC50 values: 41.36, 89.43, 50.66 µM) activities, possibly due to electronic effects induced by these groups. 3‐Phenyl‐4‐(phenylseleno) isoquinoline (without substitution at the selenium‐bonded aromatic ring) and 4‐(4‐methylphenylseleno)‐3‐phenylisoquinoline (with a methyl group substituted at the selenium‐bonded aromatic ring) did not alter the activity of these enzymes. Dithiothreitol, a reducing agent, restored the enzymatic activities inhibited by 4‐(4‐fluorophenylseleno)‐3‐phenylisoquinoline, 4‐(4‐chlorophenylseleno)‐3‐phenylisoquinoline and 4‐(3‐trifluoromethylphenylseleno)‐3‐phenylisoquinoline, suggesting the involvement of sulfhydryl residues in this effect. However, the release of essential zinc seems not to be related to the δ‐ALA‐D inhibition by these compounds. According to these data, the effect of oral administration (300 mg/kg, intragastric) of 3‐phenyl‐4‐(phenylseleno) isoquinoline on markers of systemic toxicity in Wistar rats was evaluated. None signs of toxicity was observed during or after treatment. This study suggests that the insertion of electron‐withdrawing groups in the aromatic ring bonded to the selenium atom of isoquinolines tested increased its inhibitory effect on sulfhydryl enzymes in vitro. 3‐Phenyl‐4‐(phenylseleno) isoquinoline, which has documented pharmacological properties, had no toxicological effects on the parameters evaluated in this study. J. Cell. Biochem. 118: 1144–1150, 2017.