Effects of Ring Size and Polar Functional Groups on the Glutathione Peroxidase-Like Antioxidant Activity of Water-Soluble Cyclic Selenides

Abstract

To elucidate the effects of ring structure and a substituent on the glutathione peroxidase- (GPx-) like antioxidant activities of aliphatic selenides, series of water-soluble cyclic selenides with variable ring size and polar functional groups were synthesized, and their antioxidant activities were evaluated by NADPH-coupled assay using H2O2 and glutathione (GSH) in water and also by NMR spectroscopy using H2O2 and dithiothreitol (DTT(red)) in methanol. Strong correlations were found among the GPx-like activity in water, the second-order rate constants for the oxidation of the selenides, and the HOMO energy levels calculated in water. The results support the conclusion that the oxidation process is the rate-determining step of the catalytic cycle. On the other hand, such correlations were not obtained for the activity observed in methanol. The optimal ring size was determined to be five. The type of substituent (NH2 < OH < CO2H) and the number can also control the activity, whereas the stereoconfiguration has only marginal effects on the activity in water. In methanol, however, the activity rank could not be explained by the simple scenarios applicable in water.

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

“…[51] While several of the cyclic seleninates and spiroselenuranes describeda bove have improveda ctivity compared to ebselen in the indicated assays,m ost display equally poor solubility in water.I no rder to improves olubility,s elenides 36 and 38 were prepared, representing the reduced form of spiroselenuranes 37 and 39,r espectively. [52,53] These compounds retain one arylseleniumb ond in order to resist metabolic conversion into toxic inorganic species, but display much improved solubility properties. Thus, selenides 36 proved soluble in 5% ethanolwater,w hile the additional hydroxyl group in compounds 38 renderedt hem freely soluble in water alone.…”

Basic Amino Acid Conjugates of 1,2‐Diselenan‐4‐amine with Protein Disulfide Isomerase‐like Functions as a Manipulator of Protein Quality Control

“…[7b] However, such structural modifications of the simple Se-containing cyclic compounds have not been readily achieved in practical organic synthesis. [8] In addition, we have recently reported that selenenyl sulfide (SeÀ S) analogues of 1, which is a model compound of the thioredoxin reductase active center composed of C497 and selenocysteine (U) 498, catalyzes the reduction of H 2 O 2 , a reactive oxygen species, and protein SS bonds in the presence of a dithiol activator. [9] This model study revealed that neighboring His472 at the active center kinetically accelerates the reduction of the SeÀ S bond between C497 and U498, and thermodynamically stabilizes the generated reactive selenolate (Se À ) state by forming intramolecular NH *** Se hydrogen bond.…”

Diethyl Selenodiglycolate: An Eco-Friendly Synthetic Antioxidant with Potential Application to Inflammatory Disorders

“…13 Similar activities were presented by a camphor based selenamide derivative 14 and some water soluble selenides, presenting different ring sizes and organic chemical functionality classes. 15 Organoselenium compounds which act against lipid peroxidation, free radical chain reaction 16 and possess pharmacological properties have been extensively investigated. 17,18 In fact, the hypohalous acid-scavenging efficiency of some synthetic selenium-containing compounds, including selenomethionine, has been described.…”