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ADVANCES IN SELENIUM SUPPLEMENTATION

补硒方面的进展

基本信息

批准号：
6983423
负责人：
MICHAEL Roger FRANKLIN
金额：
$ 26.28万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6983423
关键词：
ADVANCES SELENIUM SUPPLEMENTATION

项目摘要

DESCRIPTION (provided by applicant): 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.

项目描述（申请人提供）：本项目拟制备并初步研究新型硒传递剂硒唑烷羧酸。硒在人类健康中越来越重要，它不仅仅是一种公认的微量营养素。例如，硒作为一种癌症化学预防剂，对多种致癌物引起的几种器官的疾病表现出令人兴奋的活性。然而，硒也以其毒性而闻名，这使得临床有价值的药物的开发成为一项独特的挑战，必须极其谨慎和创造性地完成。硒代唑烷代表了硒代半胱氨酸的“前药”形式。它们的设计目的是提供持续的氨基酸供应（作为硒的来源），其水平高且持续，足以具有治疗价值，但又不足以产生毒性。目前的应用将实现四个具体目标：(1)设计、合成和化学表征精心挑选的新亚类硒化唑烷前体药物原型，以允许发展关键的结构-活性关系；(2)了解硒代唑烷类化合物的化学/生化分解；(3)在已建立的A/J小鼠模型中进行动物实验，研究新药物的毒性及其对基本生化参数的影响；(4)扩大动物研究范围，以：(a)研究新型硒代唑烷类化合物对烟草衍生的肺癌物质的癌症化学预防活性；(b)探讨癌症化学预防的不同给药时间表；(c)研究选择硒代唑烷与维生素E、维生素c或n -乙酰半胱氨酸（半胱氨酸来源）联合使用以增强化学预防；(d)研究选定的硒偶氮烷类化合物对缺硒动物的预防作用。这些类似物是完全新颖的；这似乎是硒领域的一种全新方法，并可能使硒作为预防和/或治疗人类疾病的药物的潜力在临床上得以实现。