Fluoxetine scaffold to design tandem molecular antioxidants and green catalysts

Ribaudo, Giovanni; Bortoli, Marco; Ongaro, Alberto; Oselladore, Erika; Gianoncelli, Alessandra; Zagotto, Giuseppe; Orian, Laura

doi:10.1039/d0ra03509b

Cited by 21 publications

(46 citation statements)

References 82 publications

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“…The reaction is initiated by the oxidation of the selenium atom to the corresponding selenoxide, a step which can be induced by different agents such as hydrogen peroxide, meta-chloroperoxybenzoic acid (mCPBA) and ozone [ 7 , 16 , 17 ]. Then, an intramolecular syn elimination takes place: the Se-C bond breaks producing the trans -olefin and selenenic acid, that is readily oxidized to seleninic acid [ 10 ]. Interestingly, in the case of the studied compounds ( Scheme 2 ), an enamine is produced after the oxidation–elimination step.…”

Section: Resultsmentioning

confidence: 99%

“…Then, an intramolecular syn elimination occurs in opportune substrates, involving the hydrogen atom in vicinal position with respect to the selenium nucleus. This leads to the formation of the corresponding trans -olefine [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the context of our studies on selenium-based derivatives of compounds of pharmaceutical interest, we observed a peculiar behavior of amino organoselenides [ 10 ]. In particular, under oxidative conditions, we previously detected the formation of primary and secondary amines from mono- or disubstituted 2-phenyl-2-(phenylselanyl)ethan-1-amines ( Scheme 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, we previously showed that compounds endowed with bioactivity can be generated after release from such substrates. Molecules selectively providing elimination products in response to oxidative stress represent attractive tools, in particular in the context of central nervous system (CNS) drugs [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Selenoxide Elimination Triggers Enamine Hydrolysis to Primary and Secondary Amines: A Combined Experimental and Theoretical Investigation

et al. 2021

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We discuss a novel selenium-based reaction mechanism consisting in a selenoxide elimination-triggered enamine hydrolysis. This one-pot model reaction was studied for a set of substrates. Under oxidative conditions, we observed and characterized the formation of primary and secondary amines as elimination products of such compounds, paving the way for a novel strategy to selectively release bioactive molecules. The underlying mechanism was investigated using NMR, mass spectrometry and density functional theory (DFT).

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selenoxide Elimination Triggers Enamine Hydrolysis to Primary and Secondary Amines: A Combined Experimental and Theoretical Investigation

et al. 2021

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“…This analysis shows how a very rich literature regarding the general antioxidant activity of flavonoids is paralleled by a very scarce collection of works that investigate the antioxidant properties of antidepressant and antipsychotic drugs at a molecular level. One of the few very recent contributions in this field, reported by some of the authors of this work, originated from the idea to combine the antioxidant abilities of fluoxetine and of selenium [ 153 ]. Although an oligoelement in the human body, selenium is found in some essential antioxidant enzymes such as glutathione peroxidases, iodothyronine deiodinase (DIO), thioredoxin reductases (TrxR) and methionine sulfoxide reductases (Msr) [ 154 ].…”

Section: In Silico Approachesmentioning

confidence: 99%

Antioxidant Potential of Psychotropic Drugs: From Clinical Evidence to In Vitro and In Vivo Assessment and toward a New Challenge for in Silico Molecular Design

et al. 2020

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Due to high oxygen consumption, the brain is particularly vulnerable to oxidative stress, which is considered an important element in the etiopathogenesis of several mental disorders, including schizophrenia, depression and dependencies. Despite the fact that it is not established yet whether oxidative stress is a cause or a consequence of clinic manifestations, the intake of antioxidant supplements in combination with the psychotropic therapy constitutes a valuable solution in patients’ treatment. Anyway, some drugs possess antioxidant capacity themselves and this aspect is discussed in this review, focusing on antipsychotics and antidepressants. In the context of a collection of clinical observations, in vitro and in vivo results are critically reported, often highlighting controversial aspects. Finally, a new challenge is discussed, i.e., the possibility of assessing in silico the antioxidant potential of these drugs, exploiting computational chemistry methodologies and machine learning. Despite the physiological environment being incredibly complex and the detection of meaningful oxidative stress biomarkers being all but an easy task, a rigorous and systematic analysis of the structural and reactivity properties of antioxidant drugs seems to be a promising route to better interpret therapeutic outcomes and provide elements for the rational design of novel drugs.

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Radical Scavenging Potential of the Phenothiazine Scaffold: A Computational Analysis

et al. 2021

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The reactivity of phenothiazine (PS), phenoselenazine (PSE), and phenotellurazine (PTE) with different reactive oxygen species (ROS) has been studied using density functional theory (DFT) in combination with the QM-ORSA (Quantum Mechanicsbased Test for Overall Free Radical Scavenging Activity) protocol for an accurate kinetic rate calculation. Four radical scavenging mechanisms have been screened, namely hydrogen atom transfer (HAT), radical adduct formation (RAF), single electron transfer (SET), and the direct oxidation of the chalcogen atom. The chosen ROS are HO * , HOO * , and CH 3 OO * . PS, PSE, and PTE exhibit an excellent antioxidant activity in water regardless of the ROS due to their characteristic diffusioncontrolled regime processes. For the HO * radical, the primary active reaction mechanism is, for all antioxidants, RAF. But, for HOO * and CH 3 OO * , the dominant mechanism strongly depends on the antioxidant: HAT for PS and PSE, and SET for PTE. The scavenging efficiency decreases dramatically in lipid environment and remains only significant (via RAF) for the most reactive radical (HO * ). Therefore, PS, PSE, and PTE are excellent antioxidant molecules, especially in aqueous, physiological environments where they are active against a broad spectrum of harmful radicals. There is no advantage or significant difference in the scavenging efficiency when changing the chalcogen since the reactivity mainly derives from the amino hydrogen and the aromatic sites.

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Fluoxetine scaffold to design tandem molecular antioxidants and green catalysts

Abstract: We modified fluoxetine by incorporating a selenium nucleus enabling a hydroperoxide-inactivating, glutathione peroxidase (GPx)-like activity and paving the way for its use as green catalyst.

Cited by 21 publications

References 82 publications

Selenoxide Elimination Triggers Enamine Hydrolysis to Primary and Secondary Amines: A Combined Experimental and Theoretical Investigation

Selenoxide Elimination Triggers Enamine Hydrolysis to Primary and Secondary Amines: A Combined Experimental and Theoretical Investigation

Antioxidant Potential of Psychotropic Drugs: From Clinical Evidence to In Vitro and In Vivo Assessment and toward a New Challenge for in Silico Molecular Design

Radical Scavenging Potential of the Phenothiazine Scaffold: A Computational Analysis

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