This project proposes the preparation and preliminary study of selenazolidine carboxylic acids as novel selenium delivery agents. Selenium is of growing importance in human health beyond its well-recognized role as a micronutrient. For example, selenium has exhibited exciting activity as a cancer chemopreventive agent against disease in several organs, caused by a variety of carcinogens. Selenium is also known for its toxicity, however, making the development of clinically valuable agents a distinct challenge that must be accomplished with extreme care and creativity. The selenazolidines represent """"""""prodrug"""""""" forms of Lselenocysteine. They were designed to provide a continuous supply of the amino acid (as a source of selenium) at levels high and sustained enough to have therapeutic value but not high enough to produce toxicity. The current application will accomplish four specific aims: (1) Design, synthesize, and chemically characterize carefully selected prototypes of new subclasses of selenazolidine prodrugs to allow the development of critical structure-activity relationships; (2) Understand the chemical/biochemical breakdown of the selenazolidines; (3) Undertake animal studies in the well-established A/J mouse model to study toxicity of the novel agents, as well as their effect on basic biochemical parameters; (4) Expand animal studies to: (a) investigate the cancer chemopreventive activity of the new selenazolidines against a tobacco derived lung carcinogen; (b) explore varied administration schedules for cancer chemoprevention; (c) study selected selenazolidines in combination with vitamin E, vitamin C, or N-acetylcysteine (cysteine source) to enhance chemoprevention; and (d) study the preventive attributes of selected selenazolidines in selenium-deficient animals. These analogs are completely novel; it appears to be an entirely new approach in the selenium field and may allow the potential of selenium as a preventive and/or therapeutic agent in human disease to be clinically realized.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058913-06
Application #
6983423
Study Section
Nutrition Study Section (NTN)
Program Officer
Okita, Richard T
Project Start
1998-12-01
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2009-11-30
Support Year
6
Fiscal Year
2006
Total Cost
$262,776
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Poerschke, Robyn L; Franklin, Michael R; Moos, Philip J (2008) Modulation of redox status in human lung cell lines by organoselenocompounds: selenazolidines, selenomethionine, and methylseleninic acid. Toxicol In Vitro 22:1761-7
Franklin, Michael R; Moos, Philip J; El-Sayed, Wael M et al. (2007) Pre- and post-initiation chemoprevention activity of 2-alkyl/aryl selenazolidine-4(R)-carboxylic acids against tobacco-derived nitrosamine (NNK)-induced lung tumors in the A/J mouse. Chem Biol Interact 168:211-20
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El-Sayed, Wael M; Franklin, Michael R (2006) Hepatic chemoprotective enzyme responses to 2-substituted selenazolidine-4(R)-carboxylic acids. J Biochem Mol Toxicol 20:292-301
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Li, Liang; Xie, Yang; El-Sayed, Wael M et al. (2004) Characteristics of selenazolidine prodrugs of selenocysteine: toxicity, selenium levels, and glutathione peroxidase induction in A/J mice. Life Sci 75:447-59
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