VITAMIN D--CHEMICAL AND RELATED STUDIES

维生素 D——化学及相关研究

• 批准号: 2137012
• 负责人: WILLIAM H. OKAMURA
• 金额: $ 28.2万
• 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 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2137012
• 关键词: 1,25 dihydroxycholecalciferol; chemical kinetics; chemical structure function; chemical substitution; chickens; drug design /synthesis /production; enzyme inhibitors; nutrition related tag; organometallic compounds; oxygenases; photochemistry; polyenes; saturated /unsaturated bonds; stereochemistry; vitamin D; vitamin analog; vitamin biosynthesis; vitamin metabolism

A basic premise of this study is that synthetic, mechanistic and theoretical studies of trienes will provide significant input in our understanding of the biochemical mode-of-action of vitamin D. The latter in turn should lead to a more precise and practical approach to the treatment of disease states associated with vitamin D-related metabolic disorders. The chemical synthesis developments will assist in preparing various metabolites as well as new analogs, which through structure- function analyses provide information concerning the mechanism of action of vitamin D. An understanding of chemical processes characteristic of vitamin D or model trienes from both a mechanistic and theoretical standpoint should also lead to a better understanding of the chemical/biochemical mechanism of the behavior of vitamin D and provide a forum for more effectively designing analogs. The specific aims include: (1) basic studies of [1,5] - and [1,7]-sigmatropic hydrogen shifts (wherein it is proposed to: (a) evaluate quantitatively the stereochemical demands of [1,5]- and [1,7]-H shifts through a combination of substituent effect, substrate structural variation and kinetic isotope effect studies; (b) study factors which govern lateral double bond geometries during the course of these hydrogen shifts; and (c) carry our exploratory studies of the thermal behavior of organometallic complexes of vinylallenes; (2) studies of vitamin D analogs (wherein it is proposed to : (a) chemically and biologically evaluate previtamin metabolites and analogs and their conversion to the corresponding vitamins; (b) design, synthesize and biologically evaluate inhibitors of 1alpha-hydroxylase; and (c) synthesize photoaffinity labeled analogs of vitamin D and also develop structure- function relationships for vitamin D, metabolites via studies of new analogs, particularly those with modified CD rings; and (3) synthetic studies related to vitamin D analogs and metabolites (wherein synthetic methods will be developed to more effectively implement the preceding specific aim and these will include the development of polyene sulfoxide and allenyllithium based approaches to the total or partial synthesis of vitamin D metabolites or analogs).

这项研究的一个基本前提是合成，机械和 Trienes的理论研究将在我们的 了解维生素D的生化行为。 反过 治疗与维生素D相关的代谢相关的疾病状态 疾病。 化学合成的发展将有助于准备 各种代谢产物以及新类似物，通过结构 - 功能分析提供了有关作用机理的信息 维生素D.对化学过程特征的理解 来自机械和理论的维生素D或模型 观点也应导致更好地理解 维生素D行为的化学/生化机制，并提供 更有效地设计类似物的论坛。 具体目的包括： （1）[1,5] - 和[1,7] - 含量氢的基础研究（其中 提议：（a）定量评估立体化学需求 [1,5] - 和[1,7] -H的含量通过取代效应的组合， 底物结构变异和动力学同位素效应研究； （b） 在课程过程中控制侧向双键几何的研究因素 这些氢变化； （c）我们对 乙烯基烯的有机金属复合物的热行为； （2）研究 维生素D类似物（其中提出了：（a）化学和 生物学评估预防性代谢物和类似物及其 转化为相应的维生素； （b）设计，合成和 生物学评估1α-羟化酶的抑制剂； （c）合成 光性标记为维生素D的类似物，也发展结构 - 维生素D的功能关系，通过新的研究代谢物 类似物，尤其是那些经过修饰的CD环的类似物； （3）合成 与维生素D类似物和代谢产物有关的研究（其中合成 将开发方法以更有效地实施前面 具体目标，这些目标将包括多烯亚硫氧化物的发展 以及基于艾伦利得林的​​总合成的方法 维生素D代谢物或类似物）。