Characteristics of Selenazolidine Prodrugs of Selenocysteine: Toxicity and Glutathione Peroxidase Induction in V79 Cells

Abstract

Novel selenazolidine prodrugs of selenocysteine are being developed as potential selenium delivery agents for cancer chemoprevention and other clinical uses. The 2-unsubstituted compound, selenazolidine-4(R)-carboxylic acid (l-SCA), and the 2-oxo- and 2-methyl analogues possessing d-stereochemistry (d-OSCA and d-MSCA, respectively) were synthesized and chemically characterized. l/d pairs, along with other organoselenium compounds and common inorganic forms, were studied in cultured V79 cells to understand their inherent toxicity and their ability to induce selenium-dependent glutathione peroxidase (GPx) activity, which indicates the provision of biologically available selenium. All of the selenazolidines were much less toxic to the cells than was sodium selenite (IC₅₀ ≈ 17 μM) or the parent selenolamines, l- or d-selenocystine (IC₅₀ ≈ 34 or 39 μM, respectively); OSCA was less toxic than MSCA. The stereoisomers of OSCA produced very different IC₅₀ values (l-OSCA, ∼451 μM; d-OSCA, >3000 μM), while the IC₅₀ values derived for the stereoisomers of MSCA were of the same order of magnitude (l-MSCA, ∼79 μM; d-MSCA, ∼160 μM). Compounds possessing l-stereochemistry were at least as active with respect to GPx induction as was sodium selenite (2.2-fold increase at 15 μM). l-Selenocystine produced a 4.2-fold increase in GPx activity at 30 μM, while l-SCA produced a 5.9-fold increase, followed by l-OSCA (4.6-fold) and l-MSCA (2.1-fold), all at 100 μM. Compounds possessing d-stereochemistry showed minimal ability to induce GPx activity (d-selenocystine, 1.0-fold increase; d-OSCA, 1.4-fold increase; d-MSCA, 1.3-fold increase).