Characteristics of selenazolidine prodrugs of selenocysteine: toxicity and glutathione peroxidase induction in V79 cells.
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 (IC(50) approximately 17 microM) or the parent selenolamines, L- or D-selenocystine (IC(50) approximately 34 or 39 microM, respectively); OSCA was less toxic than MSCA. The stereoisomers of OSCA produced very different IC(50) values (L-OSCA, approximately 451 microM; D-OSCA, >3000 microM), while the IC(50) values derived for the stereoisomers of MSCA were of the same order of magnitude (L-MSCA, approximately 79 microM; D-MSCA, approximately 160 microM). Compounds possessing L-stereochemistry were at least as active with respect to GPx induction as was sodium selenite (2.2-fold increase at 15 microM). L-Selenocystine produced a 4.2-fold increase in GPx activity at 30 microM, 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 microM. 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).
Short
Megan D
MD
Department of Medicinal Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, Utah 84112, USA.
Xie
Yang
Y
Li
Liang
L
Cassidy
Pamela B
PB
Roberts
Jeanette C
JC
D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D004790:Enzyme Induction; D005979:Glutathione Peroxidase / Q000096:biosynthesis*; D016566:Organoselenium Compounds / Q000378:metabolism / Q000633:toxicity*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D011392:Proline / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D017279:Selenocysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C476442:2-methylselanazolidine-4-carboxylic acid; C476441:2-oxoselenazolidine-4-carboxylic acid; D016566:Organoselenium Compounds; D011355:Prodrugs; D017279:Selenocysteine; C014811:selenaproline; D011392:Proline; D005979:Glutathione Peroxidase