Recent Advances in the Synthesis and Antioxidant Activity of Low Molecular Mass Organoselenium Molecules

Abstract

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

Keywords: ABTS; DPPH; FRAP; GPx-like; SOD; antioxidant; catalase; lipid peroxidation; organoselenium.

Figure 1

The routes of the mainly antioxidant assays for exploring the antioxidant properties of novel organoselenium compounds. The antioxidant properties can be studied in a cell through the reduction of the oxidative damage caused to DNA, proteins, and cell membranes, or by mimicking antioxidant enzymes (SOD, CAT, GPx, etc.). Additionally, the redox activity can be observed in vitro through the reduction of oxidant concentrations or synthetic radicals, such as DPPH and ABTS. Finally, oxidants can be directly measured using specific techniques, such as electron paramagnetic (spin) resonance and fluorescent probes. In the DPPH assay, after the reduction of the DPPH radical the color changes from purple to pale yellow. In the ABTS assay, upon reduction of the ABTS radical, the green color discoloration occurs. In the FRAP test, the reduction of Fe³⁺ yields a violet-blue color.

Figure 2

The Nrf2 pathway is regulated by interactions between Nrf2 and the Keap1 protein in the cytoplasm. Under basal conditions, Nrf2 expression is maintained at low levels through proteasome activity. When the level of reactive species is elevated (oxidative stress), Keap1 is modified, resulting in the accumulation and translocation of Nrf2 to the nucleus, where it binds to AREs and activates the transcription of antioxidant genes, including those coding for SOD, CAT, and GPxs. This adaptive response plays a critical role in protecting cells against damage.

Scheme 1

Synthesis of diselenoamino acid derivatives 2.

Scheme 2

Synthesis of diselenides 4.

Scheme 3

Synthesis of aniline-derived diselenides 7.

Scheme 4

Synthesis of differently substituted β-hydroxy dialkyl- and alkyl-aryl selenides.

Scheme 5

Synthesis of novel regenerable and multifunctional selenazolonamines 14 and 15.

Scheme 6

Synthesis of 3,3′-diselenodipropionic acid 17 (DSePA).

Scheme 7

Synthesis of methyl anthranilate-based organodiselenide hybrids.

Scheme 8

Synthesis of N-substituted unsymmetrical phenylselenides 26.

Scheme 9

Synthesis of novel N-methylated ebselenamine derivatives 27.

Scheme 10

Synthesis of methoxy-substituted isoselenazolones via C-Se and Se-N bond formation.

Scheme 11

Studies on the oxidation of diselenide 13b.

Scheme 12

Synthesis of 7-chloro-4-(phenylselanyl)quinoline 34 in basic medium.

Scheme 13

Synthesis of 6-organyl-5-(arylselanyl)benzo[h]quinolines 36.

Scheme 14

Synthesis of 7-chloro-4-(phenylselanyl)quinoline 34 in acidic medium.

Scheme 15

Synthesis of 3-[(4-methoxyphenyl)selanyl]-2-phenylimidazo[1,2-a]pyridine (38a).

Scheme 16

Synthesis of 3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazo[1,2-a]pyridine (38b).

Scheme 17

Copper-catalyzed 1,3-dipolar cycloaddition of azidomethyl arylselenides with alkynes.

Scheme 18

Direct selenation of N-methylindole to prepare 43a and 43b.

Scheme 19

Synthesis of selanyl-substituted pyrazoles 46.

Scheme 20

Synthesis of Cu(II) complex 47 derived from 46a.

Scheme 21

Synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles 49.

Scheme 22

Synthesis of 7-imino[1,3]selenazolo[4,5-d]pyrimidine-5(4H)-thiones 52.

Scheme 23

Synthesis of resveratrol-derivative benzoselenophenes 56.

Scheme 24

Synthesis of benzo[b]selenophenes 60 and Ebselen analogues 62.

Scheme 25

Synthesis of 2-organylselenopheno[2,3-b]pyridines 65.

Scheme 26

Synthesis of benzo[c][1,2,5]selenadiazole derivatives 69 and 70.

Scheme 27

Synthesis of imidazole-fused selenazolium and selenazinium selenocyanates.

Scheme 28

Synthesis of di-hydroxy selenides 83 and 85.

Scheme 29

Synthesis of pyrimidine-fused selenophenes 89.

Scheme 30

Synthetic route to the synthesis of α-(phenylselanyl)acetophenone 91.

Scheme 31

Synthesis of β-functionalized symmetric and non-symmetric selenides.

Scheme 32

Synthesis of SeCN and SeCF₃ derivatives.

Scheme 33

Synthesis of selenide-based azo compounds 101 and 104.

Scheme 34

Synthesis of selenium-containing amino-thymide derivatives 107.

Scheme 35

Benzeneseleninic acid in the selenofunctionalization of 2-naphthol derivatives.

Scheme 36

Synthesis of functionalized selenides 114, 115, 116, 119, and 120.

Scheme 37

Synthesis of functionalized selenides 124, 125, 128, and 129.

Scheme 38

Synthesis of phenol-substituted selenides 131, 133, and 135.

Scheme 39

Synthesis of macrocycles 138, 139, and 142–144.

Scheme 40

Synthesis of diselenide 148 and benzoselenazole 150.

Scheme 41

Synthesis of chiral selenides (R)-152 and (S)-152.

Scheme 42

Synthesis of acyl-selenoureas 156.

Scheme 43

Synthesis of selenoureas 160.

Scheme 44

Synthesis of ferrocene-functionalized selenoureas 166.

Scheme 45

Synthesis of selenylsulfides 169.

Scheme 46

Synthesis of organoselanyl α-amino phosphonates 173.

Scheme 47

Synthesis of phosphoroselenoates 175.

Scheme 48

Synthesis of cyclic P–Se compounds 178 and the releasing of H₂Se from 178a.

Scheme 49

Synthesis of allyl selenocyanates 182.

Scheme 50

Synthesis of selenocyanates 184, 185, and 186 derived of anthranilic acid.

Scheme 51

Synthesis of selenium-containing chitosan 190.

Scheme 52

Synthesis of selenazolyl-hydrazones 193.

Scheme 53

Synthesis of 2-phenyl-3-(arylselanyl)benzofurans 195.