VITAMIN D--CHEMICAL AND RELATED STUDIES

维生素 D——化学及相关研究

• 批准号: 2900124
• 负责人: WILLIAM H. OKAMURA
• 金额: $ 33.78万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900124
• 关键词: 1,25 dihydroxycholecalciferol; 25 hydroxycholecalciferol; chemical structure function; chickens; cytochrome P450; drug design /synthesis /production; enzyme inhibitors; nuclear magnetic resonance spectroscopy; nutrition related tag; polyenes; stereochemistry; steroid hormone metabolism; vitamin D; vitamin D receptors; vitamin analog; vitamin metabolism

The goal of this investigation will continue to be the development of a detailed understanding at the molecular level of the mechanism of action of vitamin D. Through the design, chemical synthesis and biological evaluation of new analogs, appropriate structural evaluation of vitamin D metabolites and biological evaluation of new analogs, appropriate structural evaluation of vitamin D metabolites and analogs, both as the free ligand and bound to host proteins, and structure-function meta analyses of our own data together with literature data,a the long term goal is to define a more precise and practical protocol for treating disease states associated with vitamin D-related endocrine disorders. From a biomedical standpoint, there are now many examples of pathological disruption of the normal state in which a drug form of vitamin D (an analog or metabolite) is proposed to be a potentially useful form of treatment, e.g. their use in treating various cancers (breast, colon and prostate cancers as well as leukemia), bone and kidney diseases (osteoporosis, renal osteodystrophy), skin diseases (psoriasis), neurological disorders (Alzheimer's disease), problems associated with the immune system (graft rejection and several autoimmune diseases) and also AIDS). The design of analogs to selectively interact with and then activate target tissues, presumably via a receptor mediated mechanism, is a continuing goal of medicinal chemistry. Structure determines function--it is this underlying thesis upon which this proposal is based. The specific aims of this proposal include; Aim 1, which concerns the chemical synthesis and nuclear magnetic resonance (NMR) spectroscopic investigations of protein bound, multiple C-13 labeled vitamin D metabolites [vitamin D3 (D3); 25- hydroxyvitamin D3 (25-D3); and 1alpha,25-dihydroxyvitamin D3 (1,25-D3)] as a means of assessing whether 6-s-cis or 6-s-trans conformations of ligand are involved in protein binding; Aim 2, which pertains tot he design and chemical synthesis and evaluation of 6-s-cis and related analogs of 1,25-D3 and other metabolites; Aim A-3, which addresses the problem of the design, chemical synthesis and biochemical evaluation of inhibitors of 25- hydroxyvitamin D3-1alpha-hydroxylase (25-D3-1-OHase), the key enzyme involved in the final step ina the metabolic activation of 25-D into its hormonally active form, 1,25-D3, and other aspects of vitamin D metabolism; Aim 4, which concerns studies of selected agonists and antagonists of vitamin D receptors; and Aim 5, which is expected to lead to the development of stereoselective chemical methods for synthesizing vitamin D and related polyenes.

这项调查的目的将继续是发展 在分子水平上的详细理解的作用机理 维生素D.通过设计，化学合成和生物学 评估新类似物，维生素D的适当结构评估 新类似物的代谢物和生物学评估，适当 维生素D代谢产物和类似物的结构评估都是 游离配体并绑定宿主蛋白质和结构功能元 分析我们自己的数据以及文献数据，这是一个长期目标 是定义治疗疾病的更精确，更实用的方案 与维生素D相关的内分泌疾病相关的状态。 来自 生物医学的角度，现在有许多病理的例子 毒品D的正常状态破坏维生素D的正常状态（类似物 或代谢物）被认为是一种潜在有用的治疗形式 例如它们用于治疗各种癌症（乳房，结肠和前列腺 癌症以及白血病），骨骼和肾脏疾病（骨质疏松症，肾脏病 骨营养不良），皮肤病（牛皮癣），神经系统疾病 （阿尔茨海默氏病），与免疫系统有关的问题（移植物 拒绝和几种自身免疫性疾病）和艾滋病）。 设计 类似于选择性相互作用，然后激活目标组织， 大概是通过受体介导的机制，是一个持续的目标 药物化学。 结构决定功能 - 这是基础 该提议所基于的论文。 这个特定的目的 提案包括； AIM 1，涉及化学合成和核 磁共振（NMR）蛋白结合的光谱研究， 多种C-13标记为维生素D代谢产物[维生素D3（D3）; 25- 羟基维生素D3（25-D3）;和1alpha，25-二羟基维生素D3（1,25-d3）] 评估配体的6-S-S-CIS还是6-S-S-TRANS构象 参与蛋白质结合； AIM 2，这与他的设计有关 1,25-D3的6-S-CI和相关类似物的化学合成和评估 和其他代谢物； AIM A-3，解决了设计问题， 化学合成和生化评估25--的抑制剂 羟基维生素D3-1alpha-羟化酶（25-d3-1-鹰骨），关键酶 参与最后一步 激素活性形式，1,25-D3和维生素D代谢的其他方面； AIM 4，涉及对选定激动剂和拮抗剂的研究 维生素D受体；和目标5，这将导致 开发用于合成维生素D的立体选择化学方法 和相关的多烯。