Characteristics of selenazolidine prodrugs of selenocysteine: Toxicity and glutathione peroxidase induction in V79 cells

Megan D. Short, Yang Xie, Liang Li, Pamela Cassidy, Jeanette C. Roberts

Research output: Contribution to journalArticle

33 Citations (Scopus)

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).

Original languageEnglish (US)
Pages (from-to)3308-3313
Number of pages6
JournalJournal of Medicinal Chemistry
Volume46
Issue number15
DOIs
StatePublished - Jul 17 2003
Externally publishedYes

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Selenocysteine
Prodrugs
Glutathione Peroxidase
Stereochemistry
Inhibitory Concentration 50
Toxicity
Selenium
Sodium Selenite
Stereoisomerism
Poisons
Organoselenium Compounds
Chemoprevention
Carboxylic Acids
Cultured Cells
selenocystine
Neoplasms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Characteristics of selenazolidine prodrugs of selenocysteine : Toxicity and glutathione peroxidase induction in V79 cells. / Short, Megan D.; Xie, Yang; Li, Liang; Cassidy, Pamela; Roberts, Jeanette C.

In: Journal of Medicinal Chemistry, Vol. 46, No. 15, 17.07.2003, p. 3308-3313.

Research output: Contribution to journalArticle

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