ADVANCES IN SELENIUM SUPPLEMENTATION

补硒方面的进展

• 批准号: 6574471
• 负责人: JEANETTE C ROBERTS
• 金额: $ 23.51万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574471
• 关键词: acetylcysteine; aminoacid analog; ascorbate; biochemistry; cancer prevention; carcinogens; chemoprevention; combination chemotherapy; dietary supplements; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; lung neoplasms; nuclear magnetic resonance spectroscopy; nutrition related tag; prodrugs; proline; selenium; tobacco; tocopherols; toxicology

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.

描述（申请人提供）：本项目提出硒唑烷羧酸作为新型硒输送剂的制备和初步研究。硒对人类健康的重要性日益增强，超越了其作为微量营养素的公认作用。例如，硒作为癌症化学预防剂，对多种致癌物引起的多种器官疾病表现出令人兴奋的活性。然而，硒也因其毒性而闻名，这使得开发具有临床价值的药物成为一项独特的挑战，必须以极其谨慎和创造力来完成。硒唑烷代表硒代半胱氨酸的“前药”形式。它们的设计目的是提供连续供应的氨基酸（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。目前的申请将实现四个具体目标：（1）设计、合成和化学表征精心挑选的硒唑烷前药新亚类原型，以允许发展关键的结构-活性关系； (2) 了解硒唑烷的化学/生化分解； (3) 在成熟的A/J小鼠模型中进行动物研究，研究新药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) 研究新型硒唑烷对烟草衍生的肺癌致癌物的癌症化学预防活性； (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）的组合，以增强化学预防； (d) 研究选定的硒唑烷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，并且可能使硒作为人类疾病预防和/或治疗剂的潜力在临床上得以实现。