ADVANCES IN SELENIUM SUPPLEMENTATION

描述(申请人提供)：本项目提出了作为新型硒递送剂的硒唑烷羧酸的制备和初步研究。除了公认的微量营养素的作用外，硒对人类健康的重要性也越来越大。例如，硒已显示出令人兴奋的活性，作为一种癌症化学防御剂，可以预防由多种致癌物引起的几个器官的疾病。然而，硒的毒性也是众所周知的，这使得开发具有临床价值的药物成为一个独特的挑战，必须以极端的谨慎和创造力来完成。亚硒唑烷代表亚硒半胱氨酸的“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)，水平足够高和持续到足以具有治疗价值，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、合成和化学表征精选的新亚类硒唑烷前药的原型，以便建立关键的结构-活性关系；(2)了解硒的化学/生化分解；(3)在已建立的A/J小鼠模型中进行动物研究，以研究新制剂的毒性及其对基本生化参数的影响；(4)扩大动物研究范围：(A)调查新硒唑烷对烟草来源的肺癌致癌物的化学预防活性；(B)探索癌症化学预防的不同给药方案；(C)研究选定的硒与维生素E、维生素C或N-乙酰半胱氨酸(半胱氨酸来源)相结合以加强化学预防；以及(D)研究选定的硒在缺硒动物中的预防属性。这些类似物是完全新颖的；它似乎是硒领域的一种全新的方法，并可能使硒作为人类疾病预防和/或治疗剂的潜力在临床上实现。

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.