A series of new chiral benzisoselenazol-3(2H)-ones and their corresponding diselenides bearing an o-amido function substituted on the nitrogen atom with various aliphatic and aromatic moieties were synthesized. All derivatives representing pairs of enantiomers or diastereoisomers were obtained to thoroughly evaluate the three-dimensional structure–activity correlation. First, bensisoselenazol-3(2H)-ones were synthesized by reacting 2-(chloroseleno)benzoyl chloride with an appropriate enantiomerically pure amine. Then, the Se–N bond was cleaved by a reduction–oxidation procedure using sodium borohydride and then air oxidation to obtain the corresponding diselenides. All derivatives were tested as antioxidants and anticancer agents. In general, the diselenides were more reactive peroxide scavengers, with the highest activity observed for 2,2′-diselenobis[N-(1S,2S)-(-)-trans-2-hydroksy-1-indanylbezamide]. The most cytotoxic derivative towards human promyelocytic leukemia HL-60 and breast cancer MCF-7 cell lines was N-[(1S,2R)-(-)-cis-2-hydroksy-1-indanyl]-1,2-benzizoselenazol-3(2H)-one. The structure–activity relationship of the obtained organoselenium derivatives was discussed.

Organoselenium compounds are well-known glutathione peroxidase (GPx) mimetics that possess antioxidants/prooxidant properties and are able to modulate the concentration of reactive oxygen species (ROS), preventing oxidative stress in normal cells or inducing ROS formation in cancer cells leading to apoptosis. The purpose of this study was the synthesis of potent GPx mimics with antioxidant and anticancer activity along with improved bioavailability, as a result of good solubility in protic solvents. As a result of our research, glutathione peroxidase (GPx) mimetics in the form of water-soluble benzeneseleninic acid salts were obtained. The procedure was based on the synthesis of 2-(N-alkylcarboxyamido)benzeneselenenic acids, through the oxidation of benzisoselenazol-3(2H)-ones or analogous arenediselenides with an amido group, which were further converted to corresponding potassium salts by the treatment with potassium tert-butanolate. All derivatives were tested as potential antioxidants and anticancer agents. The areneseleninic acid salts were significantly better peroxide scavengers than analogous acids and the well-known organoselenium antioxidant ebselen. The highest activity was observed for the 2-(N-ethylcarboxyamido)benzeneselenenic acid potassium salt. The strongest cytotoxic effect against breast cancer (MCF-7) and human promyelocytic leukemia (HL-60) cell lines was found for 2-(N-cyclohexylcarboxyamido)benzeneselenenic acid potassium salt and the 2-(N-ethylcarboxyamido)benzeneselenenic acid, respectively. The structure–activity correlations, including the differences in reactivity of benzeneseleninic acids and corresponding salts were evaluated.

A series of unsymmetrical phenyl β-carbonyl selenides with o-amido function substituted on the nitrogen atom with chiral alkyl groups was obtained. The compounds form a series of enantiomeric and diastereomeric pairs and present the first examples of this type of chiral Se derivatives. All obtained selenides were further evaluated as antioxidants and anticancer agents to define the influence of the particular stereochemistry of the attached functional groups on the bioactivity of the molecules. The highest H₂O₂ reduction potential was observed for N-(cis-2-hydroxy-1-indanyl)-2-((2-oxopropyl)selanyl)benzamide, and the best radical scavenging properties for N-(-1-hydroxy-2-butanyl)-2-((2-oxopropyl)selanyl)benzamide. Also, both enantiomers of the N-(1-hydroxy-2-butanyl) selenide expressed the highest cytotoxic potential towards human promyelocytic leukemia HL-60 cell line with similar IC₅₀ values 14.4 ± 0.5 and 16.2 ± 1.1 µM, respectively. On the other hand, breast cancer cell line MCF-7 was most sensitive to N-((R)-(-)-1-hydroxy-2-butanyl)- 2-((2-oxopropyl)selanyl)benzamide (IC50 of 35.7 ± 0.6 µM). The structure–activity dependence of the obtained Se derivatives was discussed, and the most potent compounds were selected.

A series of phenyl β-carbonyl selenides with o-ester functionality substituted on the oxygen atom with chiral and achiral alkyl groups was synthesized. All compounds are the first examples of this type of organoselenium derivatives with an ester substituent in the ortho position. The obtained derivatives were tested as antioxidants and anticancer agents to see the influence of an ester functionality on the bioactivity of β-carbonyl selenides by replacing the o-amide group with an o-ester group. The best results as an antioxidant agent were observed for O-((1R,2S,5R)-(−)-2-isopropyl-5-methylcyclohexyl)-2-((2-oxopropyl)selanyl)benzoate. The most cytotoxic derivative against breast cancer MCF-7 cell lines was O-(methyl)-2-((2-oxopropyl)selanyl)benzoate and against human promyelocytic leukemia HL-60 was O-(2-pentyl)-2-((2-oxopropyl)selanyl)benzoate.

A series of new bidentate N,S-ligands—aziridines containing a para-substituted phenyl sulfide group—was synthesized and evaluated in the Pd-catalyzed Tsuji–Trost reaction and addition of diethylzinc and phenylethynylzinc to benzaldehyde. A high enantiomeric ratio for the addition reactions (up to 94.2:5.8) was obtained using the aziridine ligand bearing a p-nitro phenyl sulfide group. Collected results reveal a specific electronic effect that, by the presence of particular electron-donating or electron-withdrawing groups in the PhS- moiety, influences the σ-donor–metal binding and the enantioselectivity of the catalyzed reactions.

Designing a highly active and selective Se-therapeutic that mimics the activity of the antioxidant enzyme glutathione peroxidase (GPx) still remains a challenge. Since the discovery of ebselen (N-phenyl-1,2-benzisoselenazol-3(2H)-one) and its ability to act as a GPx mimetic, the search for more effective peroxide scavengers has become a “hot topic” in this field of research. Herein, we present several modifications of the benzisoselenazolone core that enable improving the antioxidant and anticancer potential of the basic ebselen structure. These transformations include (a) the installation of chiral terpene skeletons, from p-menthane, pinane, and carane systems, on the nitrogen atom; (b) exchange of the carbonyl oxygen atom for sulfur to obtain thiocarbonyl derivatives; (c) oxidation of the selenium moiety resulting in a series of benzenoselenenic acids and their further transformation to corresponding water-soluble potassium salts; and (d) attachment of an additional phenyl group leading to variously N-substituted unsymmetrical phenylselenides with an o-amido function. All of the synthetized compounds were tested as antioxidants and antiproliferative agents. Conclusions concerning the structure–activity correlation, including the difference in the reactivity of specific Se-moieties (-Se-N-, -SeOOH, -SeOOK, -SePh), N-substituents (the influence of bulky aliphatic moiety and the three-dimensional orientation of atoms), and incorporated heteroatoms (-C=O, -C=S) are presented.